Compositions and methods to prevent toxicity induced by nonsteroidal antiflammatory drugs

ABSTRACT

Nonsteroidal antiinflammatory drugs which have been substituted with a nitrogen monoxide group; compositions comprising (i) a nonsteroidal antiinflammatory drug, which can optionally be substituted with a nitrogen monoxide group and (ii) a compound that directly donates, transfers or releases a nitrogen monoxide group (preferably as a charged species, particularly nitrosonium); and methods of treatment of inflammation, pain, gastrointestinal lesions and/or fever using the compositions are disclosed. The compounds and compositions protect against the gastrointestinal, renal and other toxicities that are otherwise induced by nonsteroidal antiinflammatory drugs.

This application is a divisional of application Ser. No. 08/931,564,filed Sep. 16, 1997, which is a continuation of U.S. application Ser.No. 08/543,208, filed Oct. 13, 1995, issued as U.S. Pat. No. 5,703,073,which is a continuation-in-part of application Ser. No. 08/425,090,filed Apr. 19, 1995.

This invention relates to the field of "aspirin-like" or nonsteroidalantiinflammatory drug compounds and compositions that prevent, reduce orreverse the gastrointestinal, renal, and other toxicities associatedwith nonsteroidal antiinflammatory drugs.

Arena et al., WO94/12463, discloses the chemistry and pharmacology ofnitroxybutylester[(CH2)₄ --ONO₂ ] derivatives of several aryl propionicacid nonsteroidal antiinflammatory drugs including ketoprofen,flurbiprofen, suprofen, indobufen and etodolac. Studies onnitroxybutylester derivatives of flurbiprofen and ketoprofen are alsoreported in Wallace et al., Gastoenterology, 107:173-179 (1994). See,also, Cuzzolin et al., Pharmacol. Res., 29(1):89-97 (1994); Reuter etal., Life Sci. (USA), 55/1(PL1-PL8) (1994); Reuter et al.,Gastroenterology, 106(4):Suppl. A759 (1994); Wallace et al., Eur. JPharmacol., 257(3):249-255 (1994); Wallace et al., Gastroenterology,106(4):Suppl. A208 (1994); and Conforti et al, Agents-Actions,40(34):176-180 (1993). These publications uniformly examine and relyupon the use of indirectly linked nitrogen dioxide substitutions.

The present invention is based on the discovery by the inventors that itis possible to link a nitrogen monoxide group, nitric oxide (NO), to anon-steroidal antiinflammatory agent and that the resulting compoundsnot only possess potent analgesic/antiinflammatory properties but has amuch reduced potential for producing gastrointestinal lesions (ulcers).

The present invention is further based on the discovery by the inventorsthat it is possible to coadminister a nonsteroidal antiinflammatory drug(NSAID) and a compound that directly donates, releases or transfersnitrogen monoxide(preferably as a charged species, particularlynitrosonium) to prevent, reduce, or reverse the gastrointestinal, renal,and other toxicities induced by the NSAID. NSAIDs are antiinflammatory,analgesic and antipyretic compounds that act as cyclooxygenase, theenzyme responsible for the biosyntheses of the prostaglandins andcertain autocoids, inhibitors, including inhibitors of the variousisozymes of cyclooxygenase (including but not limited tocyclooxygenase-1 and -2) and as inhibitors of both cyclooxygenasie andlipoxygenase. A nitric oxide donor is a compound that contains a nitricoxide moiety and which directly releases or directly chemicallytransfers nitrogen monoxide (nitric oxide), preferably in its positivelycharged nitrosonium form, to another molecule. Nitric oxide donorsinclude but are not limited to S-nitrosothiols, nitrites,N-oxo-N-nitrosamines, and substrates of various forms of nitric oxidesynthase.

In one aspect the present invention provides a compound comprising anon-steroidal antiinflammatory agent to which is directly or indirectlylinked at least one NO group. The non-steroidal antiinflammatory agentcan, for example, be an aryl propionic acid or an enolic anilide. Theinvention also provides compositions comprising such compounds in apharmaceutically acceptable carrier.

In another aspect the invention provides a composition comprising amixture of a therapeutically effective amount of a nonsteroidalantiinflammatory agent and an NSAID toxicity reducing amount of acompound that donates, transfers or releases nitric oxide.

In another aspect the present invention provides a compositioncomprising a non-steroidal antiinflammatory agent to which is directlyor indirectly linked at least one NO group and a compound that donates,transfers or releases nitric oxide. The non-steroidal antiinflammatoryagent can, for example, be an aryl propionic acid or an enolic anilide.The invention also provides compositions comprising such compounds in apharmaceutically acceptable carrier.

In another aspect the invention provides a method for treatinginflammation, pain and/or fever in an individual in need thereof whichcomprises administering to the individual a nonsteroidalantiinflammatory agent, which may optionally be substituted with atleast one NO group, and a compound that donates, transfers or releasesnitric oxide. The NSAID or NSAID directly or indirectly linked to atleast one NO group, and nitric oxide donor can be administeredseparately or as components of the same composition.

In another aspect the invention provides a method of treatinginflammation, pain and/or fever in an individual in need thereof whichcomprises administering to the individual a composition comprising atherapeutically effective amount of an NSAID, which may optionally besubstituted with at least one NO group, and an NSAID toxicity reducingamount of a nitric oxide donor in a pharmaceutically acceptable carrier.Such compositions are discussed in more detail below.

In another aspect the invention provides a method to decrease or reversethe gastrointestinal toxicity of nonsteroidal antiinflammatory drugsadministered to an animal, particularly a human, by co-administering tosaid animal a nitric oxide donor. The NSAID and nitric oxide donor canbe administered separately or as components of the same composition.

In another aspect the invention provides a method to decrease or reversethe renal toxicity of nonsteroidal antiinflammatory drugs administeredto an animal, particularly a human, by co-administering to said animal anitric oxide donor. The NSAID and nitric oxide donor can be administeredseparately or as components of the same composition.

In another aspect the invention provides a method to accelerategastrointestinal tissue repair in an animal, particularly a human, byadministering to said animal a nitric oxide donor. The NSAID and nitricoxide donor can be administered separately or as components of the samecomposition.

The compounds and compositions of the present invention are novel andcan be utilized to treat numerous inflammatory disease states anddisorders. For example, reperfusion injury to an ischemic organ, e.g.,reperfusion injury to the ischemic myocardium, myocardial infarction,inflammatory bowel disease, rheumatoid arthritis. osteoarthritis,hypertension, psoriasis, organ transplant rejections, organpreservation, impotence, radiation-induced injury, asthma,atherosclerosis, thrombosis, platelet aggregation, metastasis,influenza, stroke, burns, trauma, acute pancreatitis, pyelonephritis,hepatitis, autoimmune diseases, insulin-dependent diabetes mellitus,disseminated intravascular coagulation, fatty embolism, Alzheimer'sdisease, adult and infantile respiratory diseases, carcinogenesis andhemorrhages in neonates.

The NSAID can be nitrosylated through sites such as oxygen (hydroxylcondensation), sulfur (sulfhydryl condensation), carbon and nitrogen.

The term "lower alkyl" herein refers to branched or straight chain alkylgroups comprising one to ten carbon atoms, including methyl, ethyl,propyl, isopropyl, n-butyl, t-butyl, neopentyl and the like.

The term "alkoxy" herein refers to RO-wherein R is lower alkyl asdefined above. Representative examples of alkoxy groups include methoxy,ethoxy, t-butoxy and the like.

The term "alkoxyalkyl" herein refers to an alkoxy group as previouslydefined appended to an alkyl group as previously defined. Examples ofalkoxyalkyl include, but are not limited to, methoxymethyl,methoxyethyl, isopropoxymethyl and the like.

The term "alkoxyalkyl" herein refers to a branched or straight chain C₂-C₁₀ hydrocarbon which also comprises one or more carbon--carbon doublebonds.

The term "amino" herein refers to --NH₂.

The term "cyano" herein refers to --CN.

The term "hydroxy" herein refers to --OH.

The term "alkylsulfinyl" herein refers to R₅₀ --S(O)₂ -- wherein R₅₀ isa branched or unbranched lower alkyl of up to four carbons.

The term "carboxamido" herein refers to --C(O)NH₂.

The term "carbamoyl" herein refers to --O--C(O)NH₂.

The term "carboxyl" herein refers to --CO₂ H.

The term "alkylamino" herein refers to R₅₁ NH-wherein R₅₁ is a loweralkyl group, for example, methylamino, ethylamino, butylamino, and thelike.

The term "dialkylamino" herein refers to R₅₂ R₅₃ N-- wherein R₅₂ and R₅₃are independently selected from lower alkyl, for example dimethylamino,diethylamino, methyl propylamino, and the like.

The term "N-alkylcarbamoyl" herein refers to --O--C(O)N(R₅₁)(H) whereinR₅₁ is as previously defined.

The term "N,N-dialkylcarbamoyl" herein refers to --O--C(O)N(R₅₂)(R₅₃)wherein R₅₂ and R₅₃ are as previously defined.

The term "nitroso" herein refers to the group --NO and "nitrosylated"refers to compounds that have been substituted therewith.

The term "aryl" herein refers to a mono- or bicyclic carbocyclic ringsystem having one or two aromatic rings including, but not limited to,phenyl, naphthyl tetrahydronaphthyl, indanyl, indenyl, and the like.Aryl groups (including bicyclic aryl groups) can be unsubstituted orsubstituted with one, two or three substituents independently selectedfrom loweralkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino,hydroxy, halo, and nitro. In addition, substituted aryl groups includetetrafluorophenyl and pentafluorophenyl.

The term "arylalkyl" herein refers to a lower alkyl radical to which isappended an aryl group. Representative arylalkyl groups include benzylphenylethyl, hydroxybenzyl, fluorobenzyl, fluorophenylethyl and thelike.

The term "arylthio" herein refers to R₅₄ S-- wherein R₅₄ is an arylgroup.

The term "cycloalkyl" herein refers to an alicyclic group comprisingfrom 3 to 7 carbon atoms including, but not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and the like.

The term "bridged cycloalkyl" herein refers to two or more cycloalkylradicals fused via adjacent or non-adjacent carbon atoms, including butnot limited to adamantyl and decahydronapthyl.

The terms "halogen" or "halo" herein refer to I Br, Cl or F. The term"haloalkyl" herein refers to a lower alkyl radical, as defined above,bearing at least one halogen substituent, for example, chloromethyl,fluoroethyl or trifluoromethyl and the like.

The term "heteroaryl" herein refers to a mono- or bi-cyclic ring systemcontaining one or two aromatic rings and containing at least onenitrogen, oxygen, or sulfur atom in an aromatic ring. Heteroaryl groups(including bicyclic heteroaryl groups) can be unsubstituted orsubstituted with one, two, or three substituents independently selectedfrom lower alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino,hydroxy, halo and nitro. Examples of heteroaryl groups include but arenot limited to pyridine, pyrazine, pyrimidine, pyridazine, pyrazole,triazole, thiazole, isothiazole, benzothiazole, benzoxazole,thiadiazole, oxazole, pyrrole, imidazole, and isoxazole.

The term "heterocyclic ring" herein refers to any 3-, 4-, 5-, 6-, or7-membered nonaromatic ring containing at least one nitrogen atom whichis bonded to an atom which is not part of the heterocyclic ring. Inaddition, the heterocyclic ring may also contain a one additionalheteroatom which may be nitrogen, oxygen, or sulfur.

The term "heterocyclic compounds" herein refers to mono and polycycliccompounds containing at least one heteroaryl or heterocyclic ring.

Compounds of the invention which have one or more asymmetric carbonatoms may exist as the optically pure enantiomers, pure diastereomers,mixtures of enantiomers, mixtures of diastereomers, racemic mixtures ofenantiomers, diastereomeric racemates or mixtures of diastereomericracemates. It is to be understood that the present invention anticipatesand includes within its scope all such isomers and mixtures thereof.

The NSAID used in the compositions of the invention can be any of thoseknown to the art, including those exemplified below.

First, despite the introduction of many new drugs, aspirin(acetylsalicylic acid) is still the most widely prescribedantiinflammatory, analgesic and antipyretic agent and is a standard forthe comparison and evaluation of all other NSAIDs. Salicylic acid itselfis so irritating that it can only be used externally. However,derivatives, particularly salicylate esters and salts, have beenprepared which provide ingestible forms of the salicylates which havethe desired antiinflammatory and other properties. In addition toaspirin which is the acetate ester of salicylic acid, are thediflurophenyl derivative (diflunisal) and salicyalicylic acid(salsalate). Also available are the salts of salicylic acid, principallysodium salicylate. Sodium salicylate and aspirin are the two mostcommonly used preparations for systemic treatment. Other salicylatesinclude salicylamide, sodium thiosalicylate, choline salicylate andmagnesium salicylate. Also available are combinations of choline andmagnesium salicylates. Also contemplated are 5-aminosalicylic acid(mesalamine), salicylazosulfapyridine (sulfasalazine) andmethylsalicylate.

Another group of NSAID drugs included are the pyramzolon derivatives.Included in this group are, for example, phenylbutazone,oxyphenbutazone, antipyrine, aminopyrine, dipyrone and apazone(azapropazone).

Another group of such NSAIDs are the para-aminophenol derivatives. Theseare the so-called "coal tar" analgesics and include phenacetin and itsactive metabolite acetaminophen.

Another group of compounds contemplated include indomethacin, amethylated indole derivative, and the structurally related compound,sulindac.

Also contemplated is a group of compounds referred to as the fenamateswhich are derivatives of N-phenylanthranilic acid. The most well knownof these compounds are mefenamic, meclofenamic, flufenamic, tolfenamicand etofenamic acids. They are used either as the acid or aspharmaceutically acceptable salts.

Another contemplated NSAID is tolmetin which, like the other NSAIDsdiscussed herein, causes gastric erosion and prolonged bleeding time.

Another group of NSAID compounds are the propionic acid derivatives.Principal members of this group are ibuprofen, naproxen, flurbiprofen,fenoprofen and ketoprofen. Other members of this group, in use or studyin countries outside the U.S., include fenbufen, pirprofen, oxaprozin,indoprofen and tiaprofenic acid.

Also contemplated are piroxicam and amperoxicam, oxicam derivativeswhich are a class of antiinflammatory enolic acids. The other relatedcompounds tenoxicam and tenidap are also contemplated. Another compoundthat is particularly contemplated is diclophenac, one of the series ofphenylacetic acid derivatives that have been developed asantiinflammatory agents. Other NSAIDs which are contemplated as suitablein the compositions of the invention include etodolac and nabumentone.

Each of the above contemplated NSAIDs is described more fully in theliterature, such as in Goodman and Gilman, The Pharmacological Basis ofTherapeutics (8th Edition), McGraw-Hill, 1993, Pgs. 638-381.

The compositions of the invention can also include NSAIDs which havebeen nitrosylated through sites such as oxygen (hydroxyl condensation),sulfur (sulfhydryl condensation), carbon and nitrogen, including thosespecifically discussed below and in the working examples that follow.

One embodiment of this aspect includes nitroso substituted compounds ofthe formula: ##STR1## wherein D is selected from (i) a covalent bond;(ii) --C(R_(a))--O--C(O)--Y--[C(R_(b))(R_(c))]_(p) --T-- in which R_(a)is lower alkyl, cycloalky, aryl or heteroaryl, Y is oxygen, sulfur, orNR_(i) in which R_(i) is hydrogen or lower alkyl, R_(b) and R_(c) areindependently selected from, hydrogen, lower alkyl, cycloalky, aryl,heteroaryl, arylalkyl, alkylamino, dialkylamino or taken together arecycloalkyl or bridged cycloalkyl, p is an integer from 1 to 6 and T is acovalent bond, oxygen, sulfur, or nitrogen; or (iii)--(CO)--T₁--[C(R_(b))(R_(c))]_(p) --T₂ -- wherein T₁ and T₂ are independentlyselected from T, and

wherein R_(b), R_(c), p and T are as defined above;

Z is an aryl or heteroaryl; and

A₁, A₂ and A₃ comprise the other subunits of a 5- or 6-memberedmonocyclic aromatic ring and each is independently selected from (1)C--R₁ wherein R₁ at each occurrence is independently selected fromhydrogen, lower alkyl, lower haloalkyl, alkoxyalkyl, halogen or nitro;(2) N--R_(d) wherein R_(d) at each occurrence is independently selectedfrom a covalent bond to an adjacent ring atom in order to render thering aromatic, hydrogen, lower alkyl, cycloalkyl, arylalkyl, aryl,heteroaryl; (3) sulfur (4) oxygen; and (5) B_(a) ═B_(b) wherein B_(a)and B_(b) are each independently selected from nitrogen or C--R₁ whereinat each occurrence R₁ is as defined above.

Another embodiment of this aspect is nitroso substituted compounds ofthe formula: ##STR2## wherein R_(b), R_(c), D, Z, A₁ , A₂ and A₃ aredefined as above.

Another embodiment is compounds of the formula: ##STR3## wherein R_(e)is hydrogen or lower alkyl;

R_(f) is selected from ##STR4## in which n is 0 or 1; and X is (1)--Y--[C(R_(b))(R_(c))]p--G--[C(R_(b))(R_(c))]p--T--NO, wherein G is (i)a covalent bond;

(ii) --T--C(O)--; (iii) --C(O)--T; (iv) --C(Y--C(O)--R_(m))-- wherein Rmis heteroaryl or heterocyclic ring; and in which Y, R_(b), R_(c), p andT are as defined above; or (2) ##STR5## in which W is a heterocyclicring or NR_(h) R_(i) wherein R_(h) and R_(i) are independently selectedfrom lower allyl, aryl or alkenyl.

Another embodiment of this aspect is compounds of the formula: ##STR6##wherein R_(g) is selected from ##STR7## and X is defined as above.

The present invention also relates to processes for preparing thecompounds of formula (I), (II), (III) or (IV) and to the intermediatesuseful in such processes.

Compounds of the present invention may be synthesized as shown inreaction Schemes I through XI presented below, in which R_(a), R_(b),R_(c), R_(d), R_(e), R_(f), R_(g), A₁, A₂, A₃, p, and Z are as definedabove or as depicted in the reaction schemes for formulas I, II, III orIV; P¹ is an oxygen protecting group and P² is a sulfur protectinggroup. The reactions are performed in solvents appropriate to thereagents and materials employed are suitable for the transformationsbeing effected. It is understood by those skilled in the art of organicsynthesis that the functionality present in the molecule must beconsistent with the chemical transformation proposed. This will, onoccasion, necessitate judgment by the routines as to the order ofsynthetic steps, protecting groups required, and deprotectionconditions. Substituents on the starting materials may be incompatiblewith some of the reaction conditions required in some of the methodsdescribed, but alternative methods and substituents compatible with thereaction conditions will be readily apparent to skilled practitioners inthe art. The use of sulfur and oxygen protecting groups is well known inthe art for protecting thiol, alcohol, and amino groups againstundesirable reactions during a synthetic procedure and many suchprotecting groups are known, c.f., T. H. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, John Wiley & Sons, New York(1991).

Nitroso compounds of formula (I) wherein A₁, A₂, A₃, R_(a), ad Z aredefined as above and an O-nitrosyated enol is represenatative of the Dgroup as defined above may be prepared according to reaction Scheme I.The enolic form of the β-keto amide of the formula 1 is reacted with asuitable nitrosylating agent such as thionyl chloride nitrite, thionyldinitrite c.f., Hakimelahi et al., Helvetica Chimica Acta, 67, 907(1984), or nitrosium tetrafluoroborate in a suitable anhydrous solventsuch as methylene chloride, tetrahydrofiuran (THF), dimethylforamide(DMF), or acetonitrile with or without am amine base such as pyridine ortriethylamine to afford the O-nitrite IA. ##STR8##

Nitroso compounds of formula (I) wherein p, A₁, A₂, A₃, R_(a), R_(b),R_(c), and Z are defined as above and an 0-nitrosylated ester isrepresentative of the D group as defined above may be prepared accordingto Scheme II. The enolic form of the b-keto amide of the formula 1 isconverted to the ester of the formula 2 wherein p, R_(b) and R_(c) aredefined as above by reaction with an appropriate protect alcoholcontaining activated acylating agent wherein P₁ is as defined above.Preferred methods for the formation of enol ester are reacting the enolwith the preformed acid chloride or symmetrical anhydride of theprotected alcohol containing acid. Preferred protecting groups for thealcohol moiety are silyl ethers such as a trimethylsilyl or atert-butyldimethylsilyl ether. Deprotection of the hydroxyl moiety(fluoride ion is the preferred method for removing silyl etherprotecting groups) followed by reaction a suitable nitrosylating agentsuch as thionyl chloride nitrite, thionyl dinitrite, or nitrosiumtetrafluoroborate in a suitable anhydrous solvent such asdichloromethane, THF, DMF, or acetonitrile with or without an amine basesuch as pyridine or triethylamine affords the compound of the formulaIB. ##STR9##

Nitroso compounds of formula (I) wherein p, A₁, A₂, A₃, R_(a), R_(b),R_(c), and Z: are defined as above and an S-nitrosyated enol ester isrepresentative of the D group as defined above may be prepared accordingto reaction Scheme III. The enolic form of the b-keto amide of theformula 1 is converted to the ester of the formula 3 wherein p, R_(b),and R_(c) are defined as above by reaction with an appropriate protectedthiol containing activated acylating agent wherein P² is as definedabove. Preferred methods for the formation of enol ester are reactingthe enol with the preformed acid chloride or symmetrical anhydride ofthe protected thiol containing acid. Preferred protecting groups for thethiol moiety are as a thioester such as a thioacetate or thiobenzoate,as a disulfide, as a thiocarbamate such as N-methoxymethylthiocarbamate, or as a thioether such as a paramethoxybenzyl thioether,a tetaahydropyranyl thioether or a S-triphenylmethyl thioether.Deprotection of the thiol moiety (zinc in dilute aqueous acid,triphenylphosphine in water and sodium borohydride are preferred methodsfor reducing disulfide groups while aqueous base is typically utilizedto hydrolyze thioesters and N-methoxymethyl thiocarbamates and mercurictrifluoroacetate, silver nitrate, or strong acids such astrifluoroacetic or hydrochloric acid and heat are used to remove aparamethoxybenzyl thioether, a tetrahydropyranyl thioether or aS-triphenylmethyl thioether group) followed by reaction with a suitablenitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite,a lower alkyl nitrite such as tert-butyl nitrite, or nitrosiumtetrafluoroborate in a suitable anhydrous solvent such as methyenechloride, ThF, DMF, or acetonitrile with or without an amine base suchas pyridine or triethylamine affords the compound of the formula IC.Alternatively, reacting this intermediate with a stoichiometric quantityof sodium nitrite in aqueous acid affords the compound of the formulaIC. ##STR10##

Nitroso compounds of formula (II) wherein p, A₁, A₂, A₃, R_(b) andR_(c), and Z are defined as above and an O-nitrosylated ester isrepresentative of the D group as defined above may be prepared accordingto Scheme IV. The enolic form of the β-keto amide of the formula 4 isconverted to the ester of the formula 5 wherein p, R_(b) and R_(c) aredefined as above by reaction with an appropriate protected alcoholcontaining activated acylating agent wherein P¹ is as defined above.Preferred methods for the formation of enol ester are reacting the enolwith the preformed acid chloride or symmetrical anhydride of theprotected alcohol containing acid. Preferred protecting groups for thealcohol moiety are silyl ethers such as a trimethylsilyl or atert-butyldimethylsilyl ether. Deprotection of the hydroxyl moiety(fluoride ion is the preferred method for removing silyl etherprotecting groups) followed by reaction a suitable nitrosylating agentsuch as thionyl chloride nitrite, thionyl dinitrite, or nitrosiumtetrafluoroborate in a suitable anhydrous solvent such asdichloromethane, THF, DMF, or acetonitrile with or without an amine basesuch as pyridine or triethylamine affords the compound of the formulaIIA. ##STR11##

Nitroso compounds of formula (II) wherein p, A₁, A₂, A₃, R_(b), R_(c),and Z are defined as above and an S-nitrosyated enol ester isrepresenatative of the D group as defined above may be preparedaccording to reaction Scheme V. The enolic form of the β-keto amide ofthe formula 4 is converted to the ester of the formula 6 wherein p,R_(b) and R_(c) are defined as above by reaction with an appropriateprotected thiol containing activated acylating agent wherein P² is asdefined above. Preferred methods for the formation of enol ester arereacting the enol with the preformed acid chloride or symmetricalanhydride of the protected thiol containing acid. Preferred protectinggroups for the thiol moiety are as a thioester such as a thioacetate orthiobenzoate, as a disulfide, as a thiocarbamate such as N-methoxymethylthiocarbamate, or as a thioether such as a paramethoxybenzyl thioether,a tetrahydropyranyl thioether, or a S-triphenylmethyl thioether.Deprotection of the thiol moiety (zinc in dilute aqueous acid,triphenylphosphine in water and sodium borohydride are preferred methodsfor reducing disulfide groups while aqueous base is typically utilizedto hydrolyze thioesters and N-methoxymethyl thiocarbamates and mercurictrifluoroacetate, silver nitrate, or strong acids such astrifluoroacetic or hydrochloric acid and heat are used to remove aparamethoxybenzyl thioether, a tetrahydropyranyt thioether or aS-triphenylmethyl thioether group) followed by reaction a suitablenitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite,a lower alkyl nitrite such as tert-butyl nitrite, or nitrosiumtetrafluoroborate in a suitable anhydrous solvent such as methyenechloride, THF, DMF, or acetonitrile with or without an amine base suchas pyridine or triethylamine acid affords the compound of the formulaIIB. Alternatively, reacting this intermediate with a stiochiometricquantity of sodium nitrite in aqueous acid affords the compound of theformula IIB. ##STR12##

Nitroso compounds of formula (III) wherein p, R_(b), R_(c), R_(e) andR_(f) are defined as above and an O-nitrosylated ester is representativeof the X group as defined above may be prepared according to Scheme VI.An acid of the formula 7 is converted into the ester of the formula 8wherein p, R_(b) and R_(c) are defined as above by reaction with anappropriate monoprotected diol. Preferred methods for the preparation ofesters are initially forming the mixed anhydride via reaction of 7 witha chloroformalie such as isobutylchloroformate in the presence of a nonnucleophilic base such as triethylamine in an anhydrous inert solventsuch as dichloromethane, diethylether, or THF. The mixed anhydride isthen reacted with the monoprotected alcohol preferably in the presenceof a condensation catalyst such as 4-dimethylamine pyridine.Alternatively, the acid 7 may be first converted to the acid chloride bytreatment with oxalyl chloride in the presence of a catalytic amount ofDMF. The acid chloride is then reacted with the monoprotected alcoholpreferably in the presence of a condensation catalyst such as4-dimethylamine pyridine and a tertiary amine base such as triethylamine to afford the ester 8. Alternatively, the acid 7 and monoprotecteddiol may be coupled to afford 8 by treatment with a dehydration agentsuch as DCC. Alternatively, compound 7 may be first converted into analkali metal salt such as the sodium, potassium, or lithium salt, andreacted with an alkyl halide which also contains a protected hydroxylgroup in an polar solvent such as DMF to afford 8. Preferred protectinggroups for the alcohol moiety are silyl ethers such as a trimethylsilylor a tert-butyldimethylsilyl ether. Deprotection of the hydroxyl moiety(fluoride ion is the preferred method for removing silyl etherprotecting groups) followed by reaction with a suitable nitrosylatingagent such as thionyl chloride nitrite, thionyl dinitrite, or nitrosiumtetrafluoroborate in a suitable anhydrous solvent such asdichloromethane, THF, DMF, or acetonitrile with or without an amine basesuch as pyridine or triethylamine affords the compound of the formulaIIIA. ##STR13##

Nitroso compounds of formula (I) wherein p, R_(b), R_(c), R_(e), andR_(f) are defined as above and a S-nitrosylated ester is representativeof the X group as defined above may be prepared according to Scheme VII.An acid of the formula 7 is converted into the ester of the formula 9 byreaction with an appropriate protected thiol containing alcohol.Preferred methods for the preparation of esters are initially formingthe mixed anhydride via reaction of 7 with a chloroformate such asisobutylchloroformate in the presence of a non nucleophilic base such astriethylamine in an anhydrous inert solvent such as diethylether or THF.The mixed anhydride is then reacted with the thiol containing alcoholpreferably in the presence of a condensation catalyst such as4-dimethylamine pyridine. Alternatively, the acid 7 may be firstconverted to the acid chloride by treatment with oxalyl chloride in thepresence of a catalytic amount of DMF. The acid chloride is then reactedwith the monoprotected thiol preferably in the presence of acondensation catalyst such as 4-dimethylamine pyridine and a tertiaryamine base such as triethyl amine to afford the ester 9. Alternatively,the acid and thiol containing alcohol may be coupled to afford 9 bytreatment with a dehydration agent such as DCC. Alternatively, compound7 may be first converted into an alkali metal salt such as the sodium,potassium, or lithium salt, and reacted with an alkyl halide which alsocontains a protected thiol group in an polar solvent such as DMF toafford 9. Preferred protecting groups for the thiol moiety are as athioester such as a thioacetate or thiobenzoate, as a disulfide, as athiocarbamate such as N-methoxymethyl thiocarbamate, or as a thioethersuch as a paramethoxybenzyl thioether, a tetrahydropyranyl thioether, ora S-triphenylmethyl thioether. Deprotection of the thiol moiety (zinc indilute aqueous acid, triphenylphosphine in water and sodium borohydrideare preferred methods for reducing disulfide groups while aqueous baseis typically utilized to hydrolyze thioesters and N-methoxymethylthiocarbamates and mercuric trifluoroacetate, silver nitrate, or strongacids such as trifluoroacetic or hydrochloric acid and heat are used toremove a paramethoxybenzyl thioether, a tetrahydropyranyl thioether or aS-triphenylmethyl thioether group) followed by reaction with a suitablenitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite,a lower alkyl nitrite such as tert-butyl nitrite, or nitrosiumtetrafluoroborate in a suitable anhydrous solvent such as methylenechloride, THF, DMF, or acetonitrile with or without an amine base suchas pyridine or triethylamine affords the compound of the formula IIIB.Alternatively, this intermediate may be reacted with a stoichiometricquantity of sodium nitrite in aqueous acid affords the compound of theformula IIIB. ##STR14##

Nitroso compounds of formula (III) wherein W, R_(e), and R_(f) aredefined as above and a 6-W-substituted sydnonimine wherein W is asdefined above is representative of the X group as defined above may beprepared according to Scheme VIII. An acid of the formula 7 is convertedinto the carboximide of the formula IIIC by reaction with a6-W-substituted sydnonimine. Preferred methods for the preparation ofcarboximides are initially forming the mixed anhydride via reaction of 7with a chloroformate such as isobutylchloroformate in the presence of anon nucleophilic base such as triethylamine in an anhydrous inertsolvent such as diethylether or THF. The mixed anhydride is then reactedwith the 6-W-substituted sydnonimine to afford IIIC. Alternatively, theacid 7 may be coupled to the 6-W-substituted sydnonimine to afford IIICby treatment with a dehydration agent such as DCC. Alternatively, theacid 7 may be converted into an active ester by reaction with a suitablysubstituted phenol utilizing any of the conditions for ester formationdescribed for Scheme VI, followed by reaction with a 6-W-substitutedsydnonimine. Preferred 6-W-substituted sydnonimines are1,2,6,4-oxatriazolium, 6-amino-6-morpholine and 1,2,6,4-oxatriazolium,6-amino-6-(6-chloro-2-methyl-benzene) and preferred active esters arepara-nitrophenyl, 2,4,5-trichlorophenyl, and pentafluorophenyl.##STR15##

Nitroso compounds of formula (IV) wherein p, R_(b), R_(c), and R_(g) aredefined as above and an O-nitrosylated ester is representative of the Xgroup as defined above may be prepared according to Scheme IX. An acidof the formula 10 is converted into the ester of the formula 11 whereinp, R_(b), and R_(c) are defined as above, by reaction with anappropriate monoprotected diol. Preferred methods for the preparation ofesters are initially forming the mixed anhydride via reaction of 10 witha chloroformate such as isobutylchloroformate in the presence of a nonnucleophilic base such as triethylamine in an anhydrous inert solventsuch as dichloromethane, diethylether or THF. The mixed anhydride isthen reacted with the monoprotected alcohol preferably in the presenceof a condensation catalyst such as 4-dimethylamine pyridine.Alternatively, the acid 10 may be first converted to the acid chlorideby treatment with oxalyl chloride in the presence of a catalytic amountof DMF. The acid chloride is then reacted with the monoprotected alcoholpreferably in the presence of a condensation catalyst such as4-dimethylamine pyridine and a tertiary amine base such as triethylamineto afford the ester 11. Alternatively, the acid 10 and monoprotecteddiol may be coupled to afford 11 by treatment with a dehydration agentsuch as DCC. Alternatively, compound 10 may be first converted into analkali metal salt such as the sodium, potassium, or lithium salt, whichis then reacted With an alkyl halide which also contains a protectedhydroxyl group in an polar solvent such as DMF to afford 11. Preferredprotecting groups for the alcohol moiety are silyl ethers such as atrimethylsilyl or a tert-butyldimethylsilyl ether. Deprotection of thehydroxyl moiety (fluoride ion is the preferred method for removing silylether protecting groups) followed by reaction with a suitablenitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite,or nitrosium tetrafluoroborate in a suitable anhydrous solvent such asmethylene chloride, THF, DMF, or acetonitrile with or without an aminebase such as pyridine or triethyl amine affords the compound of theformula IVA. ##STR16##

Nitroso compounds of formula (IV) wherein R_(g) is defined as above anda S-nitrosylated ester is representative of the X group as defined abovemay be prepared according to Scheme X. An acid of the formula 10 isconverted into the ester of the formula 12 by reaction with anappropriate protected thiol containing alcohol. Preferred methods forthe preparation of esters are initially forming the mixed anhydride viareaction of 10 with a chloroformate such as isobutylchloroformate in thepresence of a non nucleophilic base such as triethylamine in ananhydrous inert solvent such as diethylether or THF. The mixed anhydrideis then reacted with than protected thiol containing alcohol preferablyin the presence of a condensation catalyst such as 4-dimethylaminepyridine. Alternatively, the acid 10 may be first converted to the acidchloride by treatment with oxalyl chloride in the presence of acatalytic amount of DMF. The acid chloride is then reacted with theprotected thiol containing alcohol preferably in the presence of acondensation catalyst such as 4-dimethylamine pyridine and a tertiaryamine base such as triethyl amine to afford the ester 12. Alternatively,the acid and protected thiol containing alcohol may be coupled to afford12 by treatment with a dehydration agent such as DCC. Alternatively,compound 10 may be first converted into an alkali metal salt such as thesodium, potassium, or lithium salt, which is then reacted with an alkylhalide which also contains a protected thiol group in an polar solventsuch as DMF to afford 12. Preferred protecting groups for the thiolmoiety are as a thioester such as a thioacetate or thiobenzoate, as adisulfide, as a thiocarbamate such as N-methoxymethyl thiocarbamate, oras a thioether such as a paramethoxybenzyl thioether, atetrahydropyranyl thioether, or a S-triphenylmethyl thioether.Deprotection of the thiol moiety (zinc in dilute aqueous acid,triphenylphosphine in water and sodium borohydride are preferred methodsfor reducing disulfide groups while aqueous base is typically utilizedto hydrolyze thioesters and N-methoxymethyl thiocarbamates and mercurictrifluoroacetate, silver nitrate, or strong acids such astrifluoroacetic or hydrochloric acid and heat are used to remove aparamethoxybenzyl thioether, a tetrahydropyranyl thioether or aS-triphenylmethyl thioether group) followed by reaction with a suitablenitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite,a lower alkyl nitrite such as tert-butyl nitrite, or nitrosiumtetrafluoroborate in a suitable anhydrous solvent such as methylenechloride, THF, DMF, or acetonitrile affords the compound of the formulaIVB. Alternatively, this intermediate may be reacted with astoichiometric quantity of sodium nitrite in aqueous acid affords thecompound of the formula IVB ##STR17##

Nitroso compounds of formula (IV) wherein R_(g) is defined as above anda 6-substituted sydnonimine is representative of the X group as definedabove may be prepared according to Scheme XI. An acid of the formula 10is converted into the carboximide of the formula IVC by reaction with a6-W-substituted sydnonimine wherein W is as defined above. Preferredmethods for the preparation of carboximides are initially forming themixed anhydride via reaction of 10 with a chloroformate such asisobutylchloroformate in the presence of a non nucleophilic base such astriethylamine in an anhydrous inert solvent such as diethylether or THF.The mixed anhydride is then reacted with the 6-W-substituted sydnonimineto afford IVC. Alternatively, the acid 10 may be coupled to the6-W-substituted sydnonimine afford IVC by treatment with a dehydrationagent such as DCC. Alternatively, the acid 10 may be converted into anactive ester by reaction with a suitably substituted phenol utilizingany of the conditions for ester formation described above, followed byreaction with a 6-W-substituted sydnonimine. Preferred 6-W-substitutedsydnonimines are 1,2,6,4-oxatriazolium, 6-amino-6-morpholine and1,2,6,4-oxatriazolium, 6-amino-6-(6-chloro-2-methyl -benzene) andpreferred active esters are para-nitrophenyl, 2,4,5-trichlorophenyl, andpentafluorophenyl. ##STR18##

The compounds that donate, transfer or release nitric oxide can be anyof those known to the art, including those mentioned and/or exemplifiedbelow.

Nitrogen monoxide can exist in three forms: NO⁻ (nitroxyl), NO• (nitricoxide) and NO⁺ (nitrosonium). NO• is a highly reactive short-livedspecies that is potentially toxic to cells. This is critical because thepharmacological efficacy of NO depends upon the form in which it isdelivered. In contrast to nitric oxide radical, nitrosonium and nitroxyldo not react with O₂ or O₂ ⁻ • species, and are also resistant todecomposition in the presence of redox metals. Consequently,administration of NO equivalents does not result in the generation oftoxic by-products or the elimination of the active NO moiety.

Compounds contemplated for use in the invention are nitric oxide andcompounds that release nitric oxide or otherwise directly or indirectlydeliver or transfer nitric oxide to a site of its activity, such as on acell membrane, in vivo. As used here, the term "nitric oxide"encompasses uncharged nitric oxide (NO•) and charged nitric oxidespecies, particularly including nitrosonium ion (NO⁺) and nitroxyl ion(NO⁻). The reactive form of nitric oxide can be provided by gaseousnitric oxide. The nitric oxide releasing, delivering or transferringcompounds, having the structure F--NO wherein F is a nitric oxidereleasing, delivering or transferring moiety, include any and all suchcompounds which provide nitric oxide to its intended site of action in aform active for their intended purpose. As used here, the term "NOadducts" encompasses any of such nitric oxide releasing, delivering ortransferring compounds, including, for example, S-nitrosothiols,S-nitroso amino acids, S-nitroso-polypeptides, and organic nitrites. Itis contemplated that any or all of these "NO adducts" can be mono- orpoly- nitrosylated at a variety of naturally susceptible or artificiallyprovided binding sites for nitric oxide.

One group of such NO adducts is the S-nitrosothiols, which are compoundsthat include at least one --S--NO group. Such compounds includeS-nitroso-polypeptides (the term "polypeptide" includes proteins andalso polyamino acids that do not possess an ascertained biologicalfunction, and derivatives thereof); S-nitrosylated amino acids(including natural and synthetic amino acids and their stereoisomers andracemic mixtures and derivatives thereof); S-nitrosated sugars,S-nitrosated-modified and unmodified oligonucleotides (preferably of atleast 5, and more particularly 5-200, nucleotides); and an S-nitrosatedhydrocarbon where the hydrocarbon can be a branched or unbranched, andsaturated or unsaturated aliphatic: hydrocarbon, or an aromatichydrocarbon; S-nitroso hydrocarbons having one or more substituentgroups in addition to the S-nitroso group; and heterocyclic compounds.S-nitrosothiols and the methods for preparing them are described in U.S.Pat. application Ser. No. 07/943,834, filed Sep. 14, 1992, Oae et al,Org. Prep. Proc. Int., 15(3):165-198 (1983); Loscalzo et al., JPhannacol. Exp. Ther., 249(3):726-729 (1989) and Kowaluk et al., J.Pharmacol. Exp. Ther., 256:1256-1264 (1990), all of which areincorporated in their entirety by reference.

One particularly preferred embodiment of this aspect relates toS-nitroso amino acids where the nitroso group is linked to a sulfurgroup of a sulfur-containing amino acid or derivative thereof. Forexample, such compounds include the following:S-nitroso-N-acetylcysteine, S-nitroso-N-acetylpenicillamine,S-nitroso-homocysteine, S-nitroso-cysteine and S-nitroso-glutathione.

Suitable S-nitrosylated proteins include thiol-containing proteins(where the NO group is attached to one or more sulfur group on an aminoacid or amino acid derivative thereof) from various functional classesincluding enzymes, such as tissue-type plasminogen activator(TPA) andcathepsin B; transport proteins, such as lipoproteins, heme proteinssuch as hemoglobin and serum albumin; and biologically protectiveproteins, such as the immunoglobulins and the cytoldnes. Suchnitrosylataed proteins are described in PCT Publ. Applic. No. WO93/09806, published May 27, 1993. Examples include polynitrosylatedalbumin where multiple thiol or other nucleophilic centers in theprotein are modified.

Further examples of suitable S-nitrosothiols include those having thestructures:

(i) CH3[C(R_(b))(R_(c))]_(x) SNO

wherein x equals 2 to 20 and R_(b) and R_(c) are as defined above;

(ii) HS[C(R_(b))(R_(c))]_(x) SNO

wherein x equals 2 to 20; and

(iii) ONS[C(R_(b))(R_(c))]_(x) Q

wherein x equals 2 to 20 and Q is selected from the group consisting offluoro, alkoxy, cyano, carboxamido, cycloalkyl, arylkoxy, alkylsulfinyl,arylthio, allylamino, dialkylamino, hydroxy, carbamoyl, N-alkylcarbamoylN,N-ialkylcarbamoyl amino, hydroxyl, carboxyl, hydrogen, nitro and aryl;and x, R_(b) and R_(c) are as defined above.

Nitrosothiols can be prepared by various methods of synthesis. Ingeneral, the thiol precursor is prepared first, then converted to theS-nitrosothiol derivative by nitrosation of the thiol group with NaNO₂under acidic conditions (pH is about 2.5) which yields the S-nitrosoderivative. Acids which may be used for this purpose include aqueoussulfuric, acetic and hydrochloric acids. Alternatively, they may benitrosated by reaction with an organic nitrite such as tert-butylnitrite, or an nitrosonium salt such as nitrosonium tetrafluoroborate inan inert solvent.

Another group of such NO adducts are those wherein the compounds donate,transfer or release nitric oxide and are selected from the groupconsisting of compounds that include at least one ON--O--, ON--N-- orON--C-- group. The compound that includes at least one ON--O--, ON--N--or ON--C-- group is preferably selected from the group consisting ofON--O--, ON--N-- or ON--C-polypeptides (the term "polypeptide" includesproteins and also polyamino acids that do not possess an ascertainedbiological function, and derivatives thereof); ON--O--, ON--N-- orON--C-amino acids (including natural and synthetic amino acids and theirstereoisomers and racemic mixtures); ON--O--, ON--N-- or ON--C-sugars;ON--O--, ON--N-- or ON--C-modified and unmodified oligonucleotides(preferably of at least 5, and more particularly 5-200, nucleotides),ON--O--, ON--N-- or ON--C-hydrocarbons which can be branched orunbranched, saturated or unsaturated aliphatic hydrocarbons or aromatichydrocarbons; ON--O--, ON--N-- or ON--C-- hydrocarbons having one ormore substituent groups in addition to the ON--O--, ON--N-- or ON--C--group; and ON--O--, ON--N-- or ON--C-heterocyclic compounds.

Another group of such adducts are N-oxo-N-nitrosamines which donate,transfer or release nitric oxide and have a R₁ R₂ --N(O_(--M) ⁺)--NOgroup wherein R₁ and R₂ include polypeptides, amino acids, sugars,modified and unmodified oligonucleotides, hydrocarbons where thehydrocarbon can be a branched or unbranched, and saturated orunsaturated aliphatic hydrocarbon or an aromatic hydrocarbon,hydrocarbons having one or more substituent groups and heterocycliccompounds. M⁺ is a metal cation, such as, for example, a Group I metalcation.

Another group of such adducts are thionitrates which donate, transfer orrelease nitric oxide and have the structure R₁ --(S)_(v) --NO wherein vis an integer of at least 2. R₁ is as described above for theN-oxo-N-nitrosamines. Preferred are the dithiols wherein v is 2.Particularly preferred are those compounds where R₁ is a polypeptide orhydrocarbon with a pair or pairs of thiols that are sufficientlystructurally proximate, i.e. vicinal, that the pair of thiols will bereduced to a disulfide. Those compounds which form disulfide speciesrelease nitroxyl ion (NO⁻) and uncharged nitric oxide (NO•). Thosecompounds where the thiol groups are not sufficiently close to formdisulfide bridges generally only provide nitric oxide as the NO⁻ formbut not as the uncharged NO• form.

Agents which stimulate endogenous NO synthesis such as L-arginine, thesubstrate for nitric oxide synthase, are also suitable for use inaccordance with the invention.

When administered in vivo, the compositions may be administered incombination with pharmaceutical carriers and in dosages describedherein.

The compositions of the present invention may be administered orally,parenterally, by inhalation spray, rectally, or topically in dosage unitformulations containing conventional nontoxic pharmaceuticallyacceptable carriers, adjuvants, and vehicles as desired. Topicaladministration may also involve the use of transdernal administrationsuch as transdermal patches or iontophoresis devices. The termparenteral as used herein includes subcutaneous injections, intravenous,intramuscular, intrasternal injection, or infusion techniques.

Solid dosage forms for oral administration may include capsules,tablets, pills, powders, granules and gels. In such solid dosage forms,the active compounds may be admixed with at least one inert diluent suchas sucrose, lactose or starch. Such dosage forms may also comprise, asin normal practice, additional substances other than inert diluents,e.g., lubricating agents such as magnesium stearate. In the case ofcapsules, tablets, and pills, the dosage forms may also comprisebuffering agents. Tablets and pills can additionally be prepared withenteric coatings.

Dosage forms for topical administration of the composition can includecreams, sprays, lotions, gels, ointments and the like. In such dosageforms the compositions of the invention can be mixed to form white,smooth, homogeneous, opaque lotions with, for example, benzyl alcohol 1%(wt/wt) as preservative, emulsifying wax, glycerin, isopropyl palmitate,lactic acid, purified water, sorbitol solution and polyethylene glycol400. They can be mixed to form a white, smooth, homogeneous, opaquecreams with, for example, benzyl alcohol 2% (wt/wt) as preservative,emulsifying wax, glycerin, isopropyl palmitate, lactic acid, purifiedwater, and sorbitol solution. They can be mixed to form ointments with,for example, benzyl alcohol 2% (wt/wt) as preservative, whitepetrolatum, emulsifying wax, and tenox II (butylated hydroxyanisole,propyl gallate, citric acid, propylene glycol). Woven pads or rolls ofbandaging material, e.g. gauge, can be impregnated with the compositionsin solution, lotion, cream, ointment or other such form can also be usedfor topical application. The compositions can also be applied topicallyusing a transdermal system, such as one of an acrylic-based polymer,adhesive with a resinous crosslinking agent impregnated with thecomposition and laminated to an impermeable backing.

Suppositories for rectal administration of the drug composition, such asfor treating pediatric fever etc., can be prepared by mixing the drugwith a suitable nonirritating excipient such as cocoa butter andpolyethylene glycols which are solid at ordinary temperatures but liquidat the rectal temperature and will therefore melt in the rectum andrelease the drug.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a nontoxic parenterally acceptable diluent or solvent,for example, as a solution in 1, 3-butanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed an a solvent or suspending medium.

While the compositions of the invention can be administered as a mixtureof an NSAID and a nitric oxide donor, they can also be used incombination with one or more additional compounds which are known to beeffective against the specific disease state that one is targeting fortreatment.

The compositions of this invention can further include conventionalexcipients, i.e., pharmaceutically acceptable organic or inorganiccarrier substances suitable for parenteral application which do notdeleteriously react with the active compounds. Suitable pharmaceuticallyacceptable carriers include, but are not limited to, water, saltsolutions, alcohol, vegetable oils, polyethylene glycols, gelatinlactose, amylose, magnesium stearate, talc, silicic acid, viscousparaffin, perfume oil, fatty acid monoglyceride and diglycerides,petroethral fatty acid esters, hydroxymethylcellulosepolyvinylpyrrolidone, etc. The pharmaceutical preparations can besterilized and if desired, mixed with auxiliary agents, e.g.,lubricants, preservatives, stabilizers, wetting agents, emulsifiers,salts for influencing osmotic pressure, buffers, colorings, flavoringand/or aromatic substances and the like which do not deleteriously reactwith the active compounds. For parenteral application, particularlysuitable vehicles consist of solutions, preferably oily or aqueoussolutions, as well as suspensions, emulsions, or implants. Aqueoussuspensions may contain substances which increase the viscosity of thesuspension and include, for example, sodium carboxymethyl cellulose.sorbitol and/or dextran. Optionally, the suspension may also containstabilizers.

The composition, if desired, can also contain minor amounts of wettingor emulsifying agents, or pH buffering agents. The composition can be aliquid solution, suspension, emulsion, tablet, pill, capsule, sustainedrelease formulation, or powder. The composition can be formulated as asuppository, with traditional binders and carriers such astriglycerides. Oral formulations can include standard carriers such aspharmaceutical grades of mannitol, lactose, starch, magnesium stearate,sodium saccharine, cellulose, magnesium carbonate, etc.

Various delivery systems are known and can be used to administer atherapeutic compound or composition of the invention, e.g.,encapsulation in liposomes, microparticles, microcapsules and the like.

The therapeutics of the invention can be formulated as neutral or saltforms. Pharmaceutically acceptable salts include, but are not limitedto, those formed with free amino groups such as those derived fromhydrochloric, phosphoric, sulfuric, acetic, oxalic, tartaric acids,etc., and those formed with free carboxyl groups such as those derivedfrom sodium, potassium, ammonium, calcium, ferric hydroxides,isopropylamine, triethylamine, 2-ethylamino ethanol, histidine,procaine, etc.

The term "therapeutically effective amount," for the purposes of theinvention, refers to the amount of the nitric oxide adduct which iseffective to achieve its intended purpose. While individual needs vary,determination of optimal ranges for effective amounts of each nitricoxide adduct is within the skill of the art Generally, the dosagerequired to provide an effective amount of the composition, and whichcan be adjusted by one of ordinary skill in the art will vary, dependingon the age, health, physical condition, sex, weight, extent of diseaseof the recipient, frequency of treatment and the nature and scope of thedisorder.

The amount of a given NSAID which will be effective in the treatment ofa particular disorder or condition will depend on the nature of thedisorder or condition, and can be determined by standard clinicaltechniques. Reference is again made to Goodman and Gilman, supra; ThePhysician's Desk Reference, Medical Economics Company, Inc., Oradell,N.J., 1995; and to Drug Facts and Comparisons, Facts and Comparisons,Inc., St. Louis, Mo., 1993. The precise dose to be employed in theformulation will also depend on the route of administration, and theseriousness of the disease or disorder, and should be decided accordingto the judgment of the practitioner and each patient's circumstances.

The amount of nitric oxide donor in a pharmaceutical composition may bein amounts of 0.1-10 times the molar equivalent of the NSAID. The usualdaily doses of NSAIDs are 3-40 mg/kg body weight and the doses of nitricoxide donors in the pharmaceutical composition may be in amounts of1-500 mg/kg body weight daily and more usually about 1-50 mg/kg.Effective doses may be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems and are in the same ranges orless than as described for the commercially available compounds in thePhysician's Desk Reference, supra.

The invention also provides a pharmaceutical pack or kit comprising oneor more containers filled with one or more of the ingredients of thepharmaceutical compositions of the invention. Associated with suchcontainer(s) can be a notice in the form prescribed by a governmentalagency regulating the manufacture, use or salt of pharmaceuticals orbiological products, which notice reflects approval by the agency ofmanufacture, use or sale for human administration.

The following non-limitative examples further describe and enable one ofordinary skill in the art to make and use the invention. Flashchromatography was performed on 40 micron silica gel (Baker).

EXAMPLE 1 Cholest-5-en-3β-O-nitroso alcohol

Cholesterol (0.242 g, 0.62 mmol) was dissolved in anhydrous methylenechloride (3 mL) and pyridine (0.103 g, 3.45 mmol) was added, followed bynitrosonium tetrafluoroborate (0.036 g, 0.31 mmol). After stirring for 1hour at room temperature an additional nitrosonium tetrluoroborate(0.099 g, 0.85 mmol) was added. The reaction mixture was stirred at roomtemperature for 16 hours. The solvent was evaporated and the residue waspurified by flash chromatography on silica gel, deactivated withtriethylamine, eluted methylene chloride to give 0.165 g (64% yield) ofthe title compound as a white solid. ¹ H NMR (CDCl₃), δ: 0.86 (d, 6 H),0.92 (d, 3 H), 1.05-1.75 (m, 21 H), 1.80-2.01 (m, 6 H), 2.25-2.47 (m, 2H), 5.23 (m, 1 H), 5 44 (m, 1 H).

EXAMPLE 2 N-(N-L-γ-glutamyl-S-Nitroso-L-cysteinyl)glycine

N-(N-L-γ-glutamyl-L-cysteinyl)glycine (100 g, 0.325 mol) was dissolvedin deoxygenated water (200 ml) and 2N HCl (162 ml) at room temperatureand then the reaction mixture was cooled to 0° C. With rapid stirring, asolution of sodium nitrite (24.4 g, 0.35 mol) in water (40 ml) was addedand stirring with cooling of the reaction mixture was continued forapproximately 1 hour after which time the pink precipitate which formedwas collected by vacuum filtration. The filter cake was resuspended inchilled 40% acetone-water (600 ml) and collected by vacuum filtration.The filter cake was washed with acetone (2×200 ml) and ether (100 ml)and then dried under high vacuum at room temperature in the dark toafford the title compound as a pink powder ¹ H NMR (D₂ O) δ: 1.98 (m,2H), 2.32 (t,2H), 3.67 (t, 1H), 3.82 (s 2H), 3.86 (dd, 1H), 3.98 (dd,1H), 4.53 (m, 1H).

EXAMPLE 3 S-Nitroso-triphenylmethanethiol

Triphenylmethyl mercaptan (0.050 g, 0.18 mmol) was dissolved inanhydrous methylene chloride and cooled to 0° C. Tert-butyl nitrite(0.186 g, 1.80 mmol) was added and the resulting mixture was stirred at0° C. for 30 min. The reaction mixture was allowed to warm to roomtemperature and stirred at room temperature for 1 hour. The solvent andexcess of tert-butyl nitrite were evaporated to give the title compoundas a green solid (0.054 g, 98%). ¹ HMR (CDCl₃) δ: 7.13-7.18 (m, 4 H),7.25-7.39 (m, 11.sub.␣ H).

EXAMPLE 4 4-O-Nitroso-1-(3-benzoyl-α-methylbenzeneacetic acid) butylester

4a. 4-Hydroxy-1-(3-benzoyl-α-methylbenzeneacetic acid) butyl ester

3-Benzoyl-α-methylbenzeneacetic acid (4 g, 16 mmol) and 100 μL DMF weredissolved in benzene (25 mL). Oxalyl chloride (1.6 mL, 18 mmol) wasadded dropwise. Stirring was continued for 2 hr before concentration toa syrup. Butanediol (9 mL, 100 mmol) and pyridine (1.67 mL, 21 mmol)were dissolved in CH₂ Cl₂ (100 mL) and dioxane (15 mL) and cooled to 0°C. A solution of the acid chloride was added in CH₂ Cl₂ (20 mL). Thereaction mixture was stirred cold for 20 min then warmed to roomtemperature with stirring for 2 hr. The solution was washed 1×30 H₂ O, 1N HCl sated NaHCO₃ and brine; dried over Na₂ S₄ ; and the volatiles wereevaporated. The residue was filtered through a pad of silica gel elutingwith 2:1 Hex:EtOAc to yield 4.8 g (91%) of hydroxy ester. ¹ H NMR(CDCl₃) δ: 7.41-7.81 (mult, 9H), 4.08-4.15 (mult, 2H), 3.79 (q, J=7.2Hz, 1H), 3.59 (t, J=6.3 Hz, 2H), 1.53-1.69 (mult, 4H), 1.53 (d, J=7.2Hz, 3H).

4b. 4-O-Nitroso-1-(3-benzoyl-α-methylbenzeneacetic acid) butyl ester

The product of Example 4a (1 g, 3.6 mmol) and pyridine (1.4 mL, 18 mmol)were dissolved in dichloromethane (15 mL) and cooled to -78° C.Nitrosonium tetrafluoroborate (840 mg, 7.2 mmol) was added and thesolution was kept cold for 30 min. The reaction was warmed to roomtemperature with continued stirring for 1 hr. The mixture was dilutedwith dichloromethane and washed with 1N HCl, then brine. The solutionwas dried over sodium sulfate and evaporated. Chromatography on silicagel eluting with 9:1 Hexane:EtOAc gave 840 mg (76%) of the titlecompound. ¹ H NMR (CDCl₃) δ: 7.41-7.80 (m, 9H), 4.65 (m, 1H), 4.11 (t,J=6.0 Hz, 2H), 3.79 (q, J=7.2 Hz, 1H), 1.65-1.72 (m, 4H), 1.53 (d, J=7.2Hz, 3H). Anal Calcd for C₂₀ H₂₁ NO₅ : C, 67.59; H, 5.96; N, 3.94. Found:C, 66.72; H, 5.95; N, 2.93

EXAMPLE 5 4-O-Nitroso-4-methyl-1-(3-benzoyl-α-methylbenzeneacetic acid)pentyl ester

5a. 4-Hydroxy-4-methyl-1-(3-benzoyl-α-methylbenzeneacetic acid) pentylester

3-Benzoyl-a-methylbenzeneacetic acid (1.99 g, 7.7 mmol) in methylenechloride (20 mL) under nitrogen and cooled over ice was treatedsuccessively with oxalyl chloride (1.36 mL, 15.7 mmol) anddimethylformamide (5 drops). A vigorous gas evolution was noted and thereaction mixture was stirred with slow warming and then overnight atambient temperature. The volatile materials were removed in vacuo andthe residue dissolved in methylene chloride (10 mL) and added dropwiseto a precooled mixture of 2-methyl-2,5-pentanediol (3.7 g, 31 mmol) andpyridine (0.69 mL, 8.6 mmol) also in methylene chloride (10 mL) under anitrogen atmosphere. The reaction mixture was stirred under nitrogenwith slow warming and then overnight at ambient temperature. Thesolution was washed successively with 2N hydrochloric acid and 2N sodiumhydroxide, dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. The residual oil was subjected to columnchromatography using ethyl acetate/hexane (1:2). The product wasisolated as an oil in 76% yield (2.1 g). ¹ H NMR (CDCl₃) δ: 7.77-7.81(m, 3H), 7.64-7.43 (m, 6H), 4.18-4.03 (m, 2H), 3.80 (q, J=7.2 Hz, 1H),1.62-1.71 (m, 2H), 1.54 (d, J=7.2 Hz, 3H), 1.42-1.35 (m, 2H), 1.16 (s,6H). Anal calcd for C₂₂ H₂₆ O₄ : C, 74.55; H, 7.39. Found: C, 74.26; H,7.43.

5b. 4-O-Nitroso-4-methyl-1-(3-benzoyl-α-methylbenzeneacetic acid) pentylester

A solution of the product of example 5a (0.4 g, 1.13 mmol) and pyridine(456 mL, 5.6 mmol) in methylene chloride (4 mL) was cooled to -78° C.and nitrosonium tetrafluoroborate (262 mg, 2.26 mmol) added. Thereaction mixture was stirred at -78° C. for 3 hours, washed with waterand dried over sodium sulfate. After filtration and evaporation of thesolvent the residual oil was subjected to column chromatography usingethyl acetate/hexane/triethylamine (18:80:2). The title compound wasisolated as an oil in 58% yield (0.25 g). ¹ H NMR (CDCl₃) δ: 7.41-7.80(m, 9H), 4.02-4.17 (m, 2H), 3.79 (q, J=7.2 Hz, 1H), 1.73-1.79 (m, 2H),1.62-1.69 (m, 2H), 1.52-1.55 (m, 9H).

EXAMPLE 6 3-S-Nitroso-3-methyl-1-(3-benzoyl-α-methylbenzeneacetic acid)butyl ester

6a. 3-Mercapto-3-methyl-1-(3-benzoyl-α-methylbenzeneacetic acid) butylester

To 3-Benzoyl-α-methylbenzeneacetic acid (529 mg, 2 mmol) in benzene (5mL) containing 5 ml of DMF was added oxalyl chloride (200 ml 2.2 mmol)dropwise. The reaction mixture was stirred 1.5 hr and then concentratedin vacuo to a syrup. The crude acid chloride was dissolved indichloromethane (10 mL) and 3-mercapto-3-methyl butanol (Sweetman et al.J. Med Chem. 14, 868 (1971) (350 mg, 2.2 mmol) was added followed bypyridine (180 ml, 2.2 mmol). The reaction was stirred at roomtemperature for 1 h and then it was diluted with dichloromethane andwash with 1N HCl, followed by saturated sodium bicarbonate, and thenbrine. The organic phase was dried over sodium sulfate, concentrated invacuo, and the residue was chromatographed on silica gel eluting with9:1 hexane:ethyl acetate to afford 640 mg (90%) of the product. ¹ H NMR(CDCl₃) δ: 7.41-7.81 (m, 9H), 4.28 (t, J=7.1 Hz, 2H), 3.78 (q, J=7.2 Hz,1H), 1.88 (t, J=7.0 Hz, 2H), 1.69 (s, 1H), 1.54 (d, J=7.3 Hz, 3H), 1.35(s, 3H), 1.34 (s, 3H).

6b. 3-S-Nitroso-3-methyl-1-(3-benzoyl-α-methylbenzeneacetic acid) butylester

To a solution of the product of Example 6a (105 mg, 0.3 mmol) indichloromethane (4 mL) was added tert-butyl nitrite (70 mg, 0.6 mmol) ina dropwise fashion. The mixture was stirred at room temperature for 30min. The solvent and excess reagent were remove in vacuo to give 113 mg(quantitative) of the title compound. ¹ H NMR (CDCl₃) δ: 7.44-7.81 (m,9H), 4.29 (t, J=6.9 Hz, 2H), 3.77 (q, j=7.2 Hz, 1H), 2.51 (t, j=6.9 Hz,2H), 1.841 (s, 3H), 1.836 (s, 3H), 1.53 (d, J=7.2 3H).

EXAMPLE 7 4-O-Nitroso-1-((S)-6-methoxy-α-methyl-2-naphthideneaceticacid) butyl ester

7a. (S)-6-methoxy-α-methyl-2-naphthaleneacetic acetyl chloride

Under a nitrogen atmosphere, oxalyl chloride (4.13 g, 30 mmol) wascombined with methylene chloride (30 mL) and the resulting mixture wascooled to 0° C. Dimethylformamide (10 drops) was added and after 5minutes of stirring, a suspension of(S)-6-methoxy-α-methyl-2-naphthaleneacetic acid (3.00 g, 13 mmol) inmethylene chloride (30 mL) was added dropwise over a 30 minute period.The reaction mixture was allowed to warm to room temperature and stirredovernight The solvent was evaporated in vacuo to give the product in aquantitative yield. ¹ H NMR (CDCl₃) δ: 1.5 (d, 3 H), 3.91 (s, 1 H), 4.21(q, 1 H), 7.09-7.14 (m, 1 H), 7.15 (d, 1 H), 7.42 (dd, 1 H), 7.68 (s, 2H), 7.71 (s, 1H).

7b. 4-Hydroxy-1-((S)-6-methoxy-α-methyl-2-naphthaleneacetic acid) butylester

Under a nitrogen atmosphere, 1,4-butanediol (5.30 mL, 60 mmol) andpyridine (0.95g, 12 mmol) were combined in methylene chloride (20 mL).The resulting solution was stirred for 5 minutes and then cooled to 0°C. A solution of the product of Example 7a (3.0 g, 12 mmol) in methylenechloride (15 ml) was added dropwise over 30 minute period. Afterstirring for 20 hours at room temperature, the reaction mixture wasdiluted with ethyl acetate and washed with 1N hydrochloric acid. Theorganic phase was dried over anhydrous sodium sulfate and concentratedin vacuo. The residue was purified by flash chromatography on silica gelusing hexane/ethyl acetate (1:1 to 1:3) to afford 3.09 g (79% yield) ofthe product as a colorless oil. ¹ H NMR (CDCl₃) δ: 1.47-1.68 (m, 4H,overlapping with a doublet at 1.57, 3H), 3.55 (t, 2H), 3.84 (q, 1H),3.91 (s, 3H), 4.11 (t, 2H), 7.11 (m, 2H), 7.15 (d, 1H), 7.42 (dd, 1H),7.67 (s, 1H), 7.70 (d, 2 H).

7c. 4-O-Nitroso-1-((S)-6-methoxy-α-methyl-2-naphthaleneacetic acid)butyl ester

The product of Example 7b (0.209 g, 0.69 mmol) was dissolved inanhydrous methylene chloride (4 mL) and pyridine (0.273 g, 3.45 mmol)was added. The resulting solution was cooled to -78° C. and nitrosoniumtetrafluoroborate (0.161 g, 1.38 mmol) was added in one portion. Thereaction mixture was stirred for 1 hour at -78° C. The solvent wasevaporated-in vacuo and the residue was purified by flash chromatographyon silica gel, deactivated with triethylamine, eluted with ethylacetate/hexane (1:2) to give 0.180 g (79% yield) of the title compoundas an oil. ¹ H NMR (CDCl₃) δ: 1.58 (d, 3H), 1.64-1.69 (m, 4H), 3.85 (q,1H), 3.92 (s, 3H), 4.11 (t, 2H), 4.60 (s, 2H), 7.10-7.13 (m, 1H), 7.15(d, 1H), 7.39 (dd, 1H), 7.66 (s, 1H), 7.70 (d, 2 H).

EXAMPLE 84-O-Nitroso-1-(1-)4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-aceticacid) butyl ester

8a.4-Hydroxy-1-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-aceticacid) butyl ester

A stirred suspension of1(4-chlorobenzoyl)5-methoxy-2-methylnonyl)-3-acetic: acid (3.7 g, 10.5mmol) in methylene chloride (20 mL) under nitrogen and cooled over icewas treated successively with oxalyl chloride (1.8 mL, 20.6 mmol) anddimethylformamide (10 drops). A vigorous gas evolution was noted and thereaction mixture was stirred with gradual warming to room temperatureand then at ambient for a total of 5 hours. The volatile materials wereremoved in vacuo and the residue dissolved in dichloromethane (10 mL)and added dropwise to a precooled mixture of 1,4-butanediol (4.7 g, 51.7mmol) and pyridine (0.92 mL, 11.4 mmol) also in methylene chloride (10mL). The reaction mixture was stirred with slow warming and. then for 5hours at ambient temperature under a nitrogen atmosphere. The solutionwas washed with 2N hydrochloric acid, saturated sodium bicarbonate,dried over anhydrous sodium sulfate, filtered and concentrated in vacuo.The residual oil was subjected to column chromatography using ethylacetate/hexane (1:2). The product was isolated as an oil in 75% yield(3.3 g ) which solidified on standing ¹ H NMR (CDCl₃) δ: 7.67 (d, J=8.4Hz, 2H), 7.47 (d, J=8.5 Hz, 2H), 6.97 (d, J=2.5 Hz, 1H), 6.87 (d, J=9Hz, 1H), 6.67 (dd, J=2.5 Hz, 9Hz, 1H), 4.13 (t, J=6.4 Hz, 2H), 3.83 (s,3H), 3.66 (s, 2H), 3.59 (t, J=6.4 Hz, 2H), 2.38 (s, 3H), 1.51-1.75 (m,4H). Anal calcd for C₂₃ H₂₄ CINO₅ : C, 64.26; H, 5.63; N, 3.26. Found:C, 64.08; H. 5.60; N, 3.18.

8b.4-O-Nitroso-1-(1-(4-chlorobenzoyl)5-methoxy-2-methyl-1-1H-indole-3-aceticacid) butyl ester

A stirred solution of the product of Example 8a (1 g, 2.3 mmol), andpyridine (0.90 mL, 11.6 mmol) in methylene chloride (15 mL) at -78° C.under a nitrogen atmosphere was treated with nitrosoniumtetrafluoroborate (0.54 g, 4.6 mmol). The reaction mixture was stirredat -78° C. for 3.5 hours, washed with water, dried with anhydrous sodiumsulfate and the solvent removed in vacuo. The residual oil was subjectedto column chromatography using ethyl acetate/hexane (1:3). The productwas isolated as a yellow oil in 69% yield (0.73 g). ¹ H NMR (CDCl₃) δ:7.66 (d, J=8.5 Hz, 2Hz), 7.47 (d, J=8.5 Hz, 2H), 6.95 (d, J=2.5 Hz, 1H),6.85 (d, J=5 Hz, 1H), 6.66 (dd, J=2.5 Hz, 6.5 Hz, 1H), 4.66 (br s, 2H),4.16 (t, J=6.6 Hz, 2H), 3.83 (s, 3H), 3.66 (s, 2H), 2.39 (s, 3H),1.65-1.80 (m, 4H). Anal calcd for C₂₃ H₂₃ ClN₂ O₆ : C, 60.2; H, 5.05; N,6.1. Found: C, 59.93; H. 4.87; N, 5.85.

EXAMPLE 93-O-Nitroso-1-(1-(4-chlorobenzoyl5-methoxy-2-methyl-1H-indole-3-aceticacid butyl ester

9a.3-Hydroxy-1-(1-(4-chlorobenzoyl)5-methoxy-2-methyl-1H-indole-3-aceticacid) butyl ester

A stirred suspension of1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid (5 g,13.9 mmol) in methylene chloride (25 mL) under nitrogen and cooled overice was treated successively with oxalyl chloride (2.44 mL, 28 mmol) anddimethylformamide (10 drops). A vigorous gas evolution was noted and thereaction mixture was stirred with gradual warming for a total of 5hours. The volatile materials were removed in vacuo and the residuedissolved in methylene chloride (15 mL) and added dropwise to aprecooled mixture (+/-)-1,3-butanediol (8.83 g, 98 mmol) and pyridine(1.24 mL, 15.4 mmol) also in dichloromethane (10 mL). The reactionmixture was stirred with slow warming and then over the weekend atambient temperature under a nitrogen atmosphere. The solution was washedwith 2N hydrochloric acid, saturated sodium bicarbonate, dried overanhydrous sodium sulfate, filtered and concentrated in vacuo. Theresidual oil was subjected to column chromatography using ethylacetate/hexane (1:1). The product was isolated as an oil whichsolidified on standing in 75% yield (4.5 g). ¹ H NMR indicated that thedesired product was contaminated with an isomer and so it wasrecrystalised three times from diethyl ether/hexanes to give the desiredproduct as a solid in 15 % yield (0.9 g). ¹ H NMR (CDCl₃) δ: 7.66 (d,J=8.5 Hz, 2H), 7.43 (d, J=8.5 Hz, 2H), 6.95 (d, J=2.4 Hz, 1H), 6.86 (d,J=9 Hz, 1H), 6.67 (dd, J=9 Hz, 2.5 Hz), 4.30-4.39 (m, 1H), 4.15-4.4 (m,1H), 3.83 (s, 3H), 3.75-3.85 (m, 1H), 3.67 (s, 2H), 2.38 (s, 3H), 1.95(s, 1H), 1.65-2.8 (m, 2H), 1.16 (d, J=6.3 Hz, 3H). Anal calcd for C₂₃H₂₄ ClNO₅ : C, 64.26; H, 5.63; N, 3.26. Found: C, 64.29; H, 5.53; N,3.18.

9b.3-O-Nitroso-1-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-aceticacid) butyl ester

A stirred solution of the product of Example 9a (0.15 g, 0.34 mmol), andpyridine (0.14 mL, 1.7 mmol) in dichloromethane (2 mL) at -78° C. undera nitrogen atmosphere was treated with nitrosonium tetrafluoroborate(0.08 g, 0.7 mmol). The reaction mixture was stirred at -78° C. for 3.5hours, washed with water, dried with anhydrous sodium sulfate and thesolvent removed in vacuo. The residual oil was subjected to columnchromatography using ethyl acetate/hexane (1:3). The title compound wasisolated as a yellow oil in 79% yield (0.125 g). ¹ H NMR (CDCl₃) δ: 7.66(d, J=8.5 Hz, 2H), 7.47 (d, J=8.5 Hz), 6.95 (d, J=2.3 Hz, 1H), 6.86 (d,J=9 Hz, 1H), 6.67 (dd, J=9 Hz, 2.5 Hz), 5.52 (sextet, J=6.5 Hz, 1H),4.06-4.24 (m, 2H), 3.83 (s, 3H), 3.65 (s, 2H), 2.38 (s, 3M), 2.05 (q,J=4 Hz, 2H), 1.37 (d, J=6.5 Hz).

EXAMPLE 10 4-O-Nitroso-4methyl-1-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-aceticacid) pentyl ester

10a.4-Hydroxy-4methyl-1-(1-(4-chlorobenzoyl-5-methoxy-2-methyl-1H-indole-3-aceticacid) pentyl ester

A stirred suspension of1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid (2.8 g,7.7 mmol) in methylene chloride (25 mL) under nitrogen and cooled overice was treated successively with oxalyl chloride (1.36 mL, 15.7 mmol)and dimethylformamide (5 drops). A vigorous gas evolution was noted andthe reaction mixture was stirred over ice for 30 min and then at roomtemperature for 3 hours. The volatile materials were removed in vacuoand the residue dissolved in methylene chloride (15 mL) and addeddropwise to a precooled mixture of 2-methyl-2,5-pentanediol (3.7 g, 31mmol) and pyridine (0.69 mL, 8.6 mmol) also in methylene chloride (10mL). The reaction mixture was stirred under nitrogen with slow warmingand then overnight at ambient temperature under a nitrogen atmosphere.The solution was washed with 2N hydrochloric acid, dried over anhydroussodium sulfate, and filtered to give an oil which was concentrated invacuo. The residual oil was subjected to column chromatography usingethyl acetate/hexane (1:2) The product was isolated as an oil whichsolidified on standing in. 100% yield (3.6 g). 1H NMR (CDCl₃) δ: 7.69(d, J=8.9 Hz, 2H), 7.47 (d, J=8.9 Hz, 2H), 6.98 (d, J=2.5 Hz, 1H), 6.87(d, J=9 Hz, 1), 6.67 (dd, J=9 Hz, 2.5 Hz), 4.09-4.14 (m, 2H), 3.83 (s,3H), 3.66 (s, 3H), 2.39 (s, 3H), 1.62-1.73 (m, 2H), 1.37-1.43 (m, 2H),1.14 (s, 6H). Anal calcd for C₂₅ H₂₈ ClNO₅ : C, 65.57; H 6.16; N, 3.06.Found: C, 65.35; H, 6.25; N, 3.10.

10b. 4-O-Nitroso-4methyl-1-(1(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid)pentyl ester

A solution of the product of Example 10a (0.2 g, 0.44 mmol) and pyridine(176 mL, 2.2 mmol) in methylene chloride (2 mL) was cooled over dry iceand nitrosonium tetrafluoroborate (101 mg, 0.87 mmol) added. Thereaction mixture was stirred at -78° C. for 3 hours, allowed to stand atthe same temperature overnight, washed with water and dried over sodiumsulfate. After filtration and evaporation of the solvent the residualoil was subjected to column chromatography (twice) using ethylacetate/hexanes/triethylamine (25:73:2). The product was isolated as anoil in 42% yield (0.09 g). ¹ H NMR (CDCl₃) δ: 7.66 (d, J=7.5 Hz, 2H),7.47 (d, J=7.5 Hz, 2H), 6.96 (d, J=2.5 Hz, 1H), 6.86 (d, J=9 Hz, 1H),6.66 (dd, J=7.5 Hz, 2.5 Hz), 4.11 (t, J=6 Hz, 2H), 3.83 (s, 3H), 3.66(s, 2H), 2.39 (s, 3H), 1.75-1.81 (m, 2H), 1.64-172 (m, 2H), 1.51 (s,6H).

EXAMPLE 113-S-Nitroso-3-methyl-1-(α-methyl-4-(2-methylpropyl)benzeneacetic acid)butyl ester

A solution of α-methyl-4-(2-methylpropyl)benzeneacetic acid (1.52 g, 7.4mmol) in methylene chloride (15 mL) cooled over ice and under nitrogen,was treated successively with oxalyl chloride (1.29 mL, 1.88 g, 14.8mmol) and dimethylformamide (5 drops). The resultant solution wasstirred over ice for 30 min and then at ambient temperature for 2 hours.The excess volatile materials were removed in vacuo and the residue,dissolved in methylene chloride (5 mL), added to a precooled solution ofpyridine (0.54 mL, 6.7 mmol) and 3-mercapto-3-methylbutanol (0.8 g, 6.7mmol) in methylene chloride (15 mL). The reaction mixture was stirredover ice for 30 min and then at ambient temperature for 3 hours. Thesolution was then diluted with additional methylene chloride and washedwith 2N hydrochloric acid, saturated sodium bicarbonate and brine andthe organic phase dried with sodium sulfate, filtered and the solventremoved in vacuo. The residual oil was subjected to columnchromatography using ethyl acetate/hexane (1:3). The product wasisolated as an oil in 68% yield (1.4 g). ¹ H NMR (CDCl₃) δ: 7.18 (d,J=7.5 Hz, 2H), 7.09 (d, J=7.5 Hz, 2H), 4.25 (t, J=6.5 Hz, 2H), 3.67 (q,J=7 z, 1H), 2.44 (d, J=7.8 Hz, 2H), 1.77-1.9 (m, 3H), 1.48 (d, J=7 Hz,3H), 1.32 (s, 6H), 0.89 (d, J=6.6 Hz, 6H).

11b. 3-S-Nitroso-3-methyl-1-(α-methyl-4(2-methylpropyl)benzeneaceticacid) butyl ester

A solution of the product of Example 11a (0.4 g, 1.2 mmol) in methylenechloride (8 mL) under nitrogen was treated with tert butyl nitrite (0.62mL, 0.53 g, 5 mmol). After stirring for 1 hour at ambient temperaturethe volatile materials were removed in vacuo. The residual green oil wassubject to column chromatography using ethyl acetate/hexanes (1:19). Theproduct was isolated as green oil in 65% yield (0.25 g). ¹ H NMR (CDCl₃)δ: 7.0 (d, J=7.5 Hz, 2H), 7.10 (d, J=7.5 Hz, 2H), 4.27 (t, J=6.9 Hz,2H), 3.66 (q, J=7.2 Hz, 1H), 2.49 (t, J=6.6 Hz, 2H), 2.44 (d, J=7.2 Hz,2H), 1.8-1.9 (m, 1H), 1.81 (s, 3H), 1.80 (s, 3H), 1.48 (d, J=7.2 Hz,3H), 0.89 (d; J=6.6 H, 6H).

EXAMPLE 12 4-O-Nitroso-1-(α-methyl-4-(2-methylpropyl)benzeneacetic acid)butyl ester

12a. 4-Hydroxy-1-(α-methyl-4-(2-methylpropyl)benzeneacetic acid) butylester

α-Methyl-4-(2-methylpropyl)benzeneacetic acid (4 g, 19 mmol) and 10 μLDMF were dissolved in benzene (30 mL). Oxalyl chloride was addeddropwise. Stirring was continued for 2 hr before concentration to asyrup. Butanediol (9 mL, 100 mmol) and pyridine (1.67 mL, 21 mmol) weredissolved in dichloromethane (100 mL) and dioxane (15 mL) and cooled to0° C. A solution of the acid chloride was added in dichloromethane (20mL). The reaction mixture was stirred cold for 20 min then warmed toroom temperature with stirring for 2 hr. The solution was washed H₂ O, 1N HCl, sated Sodium bicarbonate and finally brine; dried over sodiumsulfate; and evaporated. The residue was filtered through silica geleluting with 2:1 hexane:EtOAc to yield 4.8 g (91%) of the product. ¹ HNMR (CDCl₃) δ: 7.19 (d, J 6.2 Hz, 2H), 7.08 (d, J=8.2 Hz, 2H),4.07-4.12(m, 2H), 3.68 (q, J=7.1 Hz 1H), 3.58 (t, J=6.3 Hz, 1H), 2.44 (d, J=7.2Hz, 2H), 1.84 (sept, J=6.8 Hz, 1H), 1.50-1.69 (m, 4H), 1.48 (d, J=7.2Hz, 3H), 0.88 (d, J=6.6 Hz, 6H). Anal Calcd for C₁₇ H₂₆ O₃ : C, 73.34;H, 9.41. Found: C, 73.17; H, 9.67

12b. 4-O-Nitroso-1-(α-methyl-4-(2-methylpropyl)benzeneacetic acid) butylester

The product of Example 12a (1 g, 3.6 mmol) and pyridine (1.4 mL, 18mmol) were dissolved in dichloromethane (15 mL) and cooled to -78° C.Nitrosonium tetrafluoroborate(840 mg, 7.2 mmol) was added and thesolution was kept cold for 30 min. The reaction was warmed to roomtemperature with continued stirring for 1 hr. The mixture was dilutedwith dichloromethane and washed successively with 1N HCl, H₂ O, andbrine. The solution was dried over sodium sulfate and evaporated.Chromatography on silica gel eluting with 9:1 hexane:EtOAc gave 840 mg(76%) of the title compound. ¹ H NMR (CDCl₃) δ: 7.18 (d, J=8.1 Hz, 2H),7.08 (d, J=8.1 Hz, 2H), 4.62 (m, 2H), 4.07-4.12 (m, 2H), 3.68 (q, J=7.1Hz, 1H), 2.44 (d, J=7.2 Hz, 2H), 1.84 (sept, J=6.7 Hz, 1H), 1.64-1.68(m, 4H), 1.48 (d, J=7.2 Hz, 3H), 0.88 (d, J=6.6 Hz, 6H).

EXAMPLE 13 4-O-Nitroso-1-(2-Fluoro-α-methyl-biphenylacetic acid) butylester

13a. 2-Fluoro-α-methyl-biphenylacetic acid chloride

Under a nitrogen atmosphere, oxalyl chloride (3.8 g, 30 mmol) wascombined with methylene chloride (30 mL). The resulting mixture wascooled to 0° C. and dimethylformamide (10 drops) was added. After 5minutes of stirring a solution of 2-fluoro-α-methyl-biphenylacetic acid(3.0 g, 12 mmol) in methylene chloride (30 mL) was added dropwise over a30 minute period. The reaction mixture was allowed to warm to roomtemperature and stirred overnight The solvent was evaporated to give theproduct in a quantitative yield as a yellow solid. ¹ H NMR (CDCl₃) δ:1.58 (d, 3 H), 4.20 (q, 1 H), 7.11 (t, 2 H), 7.33-7.47 (m, 4 H), 7.54(d, 2 H).

13b. 4-Hydroxy-1-(2-Fluoro-α-methyl-biphenylacetic acid) butyl ester

Under a nitrogen atmosphere, 1,4-butanediol (5.30 mL, 60 mmol) andpyridine (0.95 g, 12 mmol) were combined in methylene chloride (20 mL).The resulting solution was stirred for 5 minutes and then cooled to 0°C. A solution of the product of Example 13a (3.0 g, 12 mmol) inmethylene chloride (15 ml) was added dropwise over 30 minute period.After stirring for 20 hours at room temperature, the reaction mixturewas diluted with ethyl acetate and washed with 1N hydrochloric acid. Theorganic phase was dried over anhydrous sodium sulfate and concentratedin vacuo. The residue was purified by flash chromatography on silica-geleluting with methylene chloride/hexane (2:1) to give 1.66 g (44%) of theproduct as a colorless oil. ¹ H NMR (CDCl₃) δ: 1.56 (d, 3 H), 1.61-1.77(m, 4 H), 3.63 (t, 2 H), 3.75 (q, 1 H), 4.14 (t, 2 H), 7.14 (t, 2 H),7.27-7.45 (m, 4 H), 7.53 (d, 2 H).

13c. 4-O-Nitroso-1-(2-Fluoro-α-methyl-biphenylacetic acid) butyl ester

The product of Example 13b (0.190 g, 0.60 mmol) was dissolved inanhydrous methylene chloride (4 mL) and pyridine (0.237 g, 3.00 mmol)was added. The resulting solution was cooled to -78° C. and nitrosoniumtetrafluoroborate (0.084 g, 0.72 mmol) was added. The reaction mixturewas stirred for 1 hour at -78° C. and an additional nitrosoniumtetrafluoroborate (0.047 g, 0.40 mmol) was added After 30 minutes ofstirring at -78° C., the solvent was evaporated in vacuo and the residuewas purified by flash chromatography on silica gel, deactivated withtriethylamine, eluted with methylene chloride/hexane (3:1) to give 0.117g (57% yield) of the title compound. ¹ H NMR (CDCl₃) δ: 1.54 (d, 3 H),1.68-1.83 (m, 4 H), 3.75 (q, 1 H), 4.14 (t, 2 H), 4.67 (s, 2 H), 7.14(t, 2 H), 7.34-7.48 (m, 4 H), 7.54 (d, 2 H).

EXAMPLE 14 4-O-Nitroso-1-(2-Fluoro-α-methyl-biphenylacetic acid)thiobutyl ester

14a. 1-tert-Butyldimethylsilyloxy-4-chloro-butanol

4-Chloro-1-butanol (5.43 g, 50 mmol) was dissolved in dimethylformamide(50 mL) and tert-butyldimethylsilylchloride (7.54 g, 50 mmol) was added,followed by imidazole (3.4 g, 50 mmol). After 24 hours of stirring atroom temperature, the reaction mixture was diluted with hexane, washedwith water and brine and dried over anhydrous sodium sulfate. Thesolvent was evaporated to give colorless liquid which was purified bychromatography on silica gel eluting with hexane/ethyl acetate (30:1) togive the product (7.26 g, 56%). ¹ H NMR (CDCl₃) δ: 0.05 (s, 6H), 0.89(s, 9 H), 1.64-1.68 (m, 2H), 1.82-1.86 (m, 2H), 3.57 (t, 2H), 3.64 (t, 2H).

14b. 4-tert-Butyldimethylsilyloxy-1-acetyl-thiobutyl ester

Under a nitrogen atmosphere, potassium thioacetate (0.53 g, 4.7 mmol)was dissolved in dimethylformamide (12 mL) and cooled to 0° C. Asolution of the product of Example 14a (1.01 g, 3.91 mmol) indimethylformamide (14 mL) was added. After 24 hours of stirring at roomtemperature, the solvent was evaporated and the residue was partitionedbetween hexane and water (1:3). The organic layer was concentrated invacuo to give the product (0.820 g, 71 %) as a yellow liquid. ¹ H NMR(CDCl₃) δ: 0.04 (s, 6H), 0.88 (s, 9 H), 1.57-1.64 (m, 4H), 2.32 (s, 3H),2.89) (t, 2H), 3.61 (t, 2 H).

14c. 4-tert-Butyldimethylsilyloxy-1-butane thiol

The product of Example 14b (5.7 g, 19.2 mmol) was dissolved in methanol(30 mL) and degassed with nitrogen gas for 30 minutes. Potassiumcarbonate (2.92 g, 21.1 mmol) was added in one portion. After 1 hour ofstarring at room temperature, the solvent was evaporated and the residuewas partitioned between hexane and water. The organic layer was driedover anhydrous sodium sulfate and concentrated in vacuo to give theproduct (3.2 g, 66%). ¹ H NMR (CDCl₃) δ: 0.05 (s, 6H), 0.89 (s, 9 H), 134 (t, 1H), 1.61-1.68 (m, 4H), 2.51-2.57 (q, 2H), 3.62 (t, 2 H).

14d. 4-tert-Butyldimethylsilyloxy-1-(2-Fluoro-α-methyl-biphenylaceticacid) thiobutyl ester

The product of Example 14c (1.37g, 5.4 mmol) was combined with pyridine(0:142 g, 1.8 mmol) in methylene chloride (5 mL) and the resultingsolution was cooled to 0° C. A solution of the product of Example 13a(0.500 g, 1.8 mmol) in methylene chloride (4 mL) was added dropwise.After 22 hours of stirring at room temperature, the reaction mixture wasdiluted with ethyl acetate and washed with 1N hydrochloric acid. Theorganic layer was dried over anhydrous sodium sulfate and concentratedin vacuo to give the product (0.526 g, 59%). ¹ H NMR (CDCl₃) δ: 0.04 (s,6H), 0.89 (s, 9H), 1.56 (d, 3H), 1.57-1.62 (m, 4H), 1.88-2.29 (M, 2H),3.61 (t, 2H), 7.15 (t, 2H), 7.37-7.44 (m, 4H), 7.54 (d, 2 H).

14e. 4-Hydroxy-1-(2-Fluoro-α-methyl-biphenylacetic acid) thiobutyl ester

The product of Example 14d (0.320 g, 0.64 mmol) was dissolved in themixture of glacial acetic acid (0.5 mL), water (1 mL), andtetrahydrofiuran (5 mL). The resulting solution was stirred for 24 hoursat room temperature. The solvent was evaporated and the residue waspartitioned between methylene chloride and water. The organic layer waswashed with saturated sodium bicarbonate solution and brine, and driedover anhydrous sodium sulfate. The solvent was evaporated to give theproduct (0.235 g, 100%). ¹ H NMR (CDCl₃) δ: 1.57 (d, 3H), 1.58-1.69 (m,4H), 2.87-293 (m, 2H), 3.63 (t, 2H), 3.84-3.92 (q, 1H), 7.14 (t, 2H),7.37-7.44. (m, 4H), 7.54 (d, 2 H).

14f. 4-O-Nitroso-1-(2-Fluoro-α-methyl-biphenylacetic acid) thiobutylester

The product of Example 14e (0.235 g, 0.61 mmol) was dissolved inanhydrous methylene chloride (3 mL) and pyridine (0.097 g, 1.23 mmol)was added. The resulting solution was cooled to -78° C. and nitrosoniumtetrafluoroborate (0.144 g, 1.23 mmol) was added in one portion. Thereaction mixture was stirred for 1 hour at -78° C., the solvent wasevaporated, and the residue was purified by chromatography on silica geleluted with hexane/ethyl acetate (10:1) to give the title compound(0.110 g, 44%). ¹ H NMR (CDCl₃) δ: 157 (d, 3H), 1.58-1.80 (m, 4H),3.85-3.93 (q, 1H), 4.69 (t, 2H), 7.14 (t, 2H), 7.37-7.44 (m, 4H), 7 55(d, 2 H).

EXAMPLE 15

4-O-Nitroso-2-methyl-N-2-pyridinyl-2-H-1,2-benzothiazine-2-carboxamide-1,1-dioxide

4-Hydroxy-2-methyl-N-2-pyridinyl-2-H-1,2-benzothiazine-2-carboxamide-1,1-dioxide(10.0 g, 30 mmol) was dissolved in anhydrous methylene chloride andcooled to 0 C. Nitrosonium tetrafluoroborate (4.407 g, 38 mmol) wasadded in one portion, followed by pyridine (2.98 g, 38 mmol). Thereaction mixture was stirred at room temperature for 7 days and thenadditional nitrosonium tetrafluoroborate (0.571 g, 1.72 mmol) was added.After stirring for 14 days at room temperature, the reaction mixture waspoured into saturated sodium bicarbonate solution and extracted withmethylene chloride. The solvent was evaporated, the residue was treatedwith ethyl acetate and filtered. The precipitate was dissolved in themixture of methylene chloride/ethylacetate (1:1), and the solution wastreated with decolorising charcoal, filtered and concentrated in vacuoto give the title compound as a solid (1.56 g, 14%). ¹ H NMR (CDCl₃, 300MHz), δ: 2.96 (s, 3 H), 6.84 (t, 1 H), 7.17 (t, 1 H), 7.60-7.86 (m, 5H), 8.22 (d, 1 H).

EXAMPLE 164-O-Nitroso-hydroxymethylene-(1-(3-benzoyl-α-methylbenzeneacetic acid))benzyl ester

16a. 3-benzoyl-α-methylbenzeneacetic acid chloride

3-Benzoyl-α-methylbenzeneacetic acid (3.2 g, 12.6 mmol) was treated inthe same manner as set forth in Example 13a. Evaporation of the solvent,afforded the product as a yellow oil in a quantitative yield. ¹ H NMR(CDCl₃), δ: 1.64 (d, 3 H), 4.21 (q, 1 H), 7.45-7.51 (m, 4 H), 7.62 (d, 1H), 7.72-7.82 (m, 4 H).

16b. 4-Hydroxymethylene-(1-(3-benzoyl-α-methylbenzeneacetic acid))benzyl ester

Under a nitrogen atmosphere, 1,4-benzenedimethanol (0.507 g, 3.67 mmol)and pyridine (0.145 g, 1.83 mmol) were combined in methylene chloride (5mL). The resulting solution was stirred for 5 minutes and then cooled to0° C. A solution of the product of Example 16a (0.500 g, 1.83 mmol) inmethylene chloride (5 mL) was added dropwise over 15 minutes. Thereaction mixture was allowed to warm to room temperature and was thenstirred over 2 days period. The solvent was evaporated and the residuewas dissolved in ethyl acetate, washed with 1N hydrochloric acid andsaturated sodium bicarbonate solution. The organic phase was dried overanhydrous sodium sulfate and concentrated in vacuo. The residue waspurified by flash chromatography on silica-gel eluting with hexane/ethylacetate (5:1 to 2:1) to give 0.092 g (42%) of the product. ¹ H NMR(CDCl₃) δ: 1.60 (d, 3 H), 2.19 (s, 1 H), 3.90 (q, 1 H), 4.71 (s, 2 H),5.17 (s, 2 H), 7.32 (dd, 4 H), 7 45-7u.82 (m, 7 H), 7 84 (d, 2 H).

16c. 4-O-Nitroso-hydroxymethylene-(1-(3-benzoyl-α-methylbenzeneaceticacid)) benzyl ester

The product of Example 16b (0.090 g, 0.24 mmol) was treated in the samemanner as set forth in Example 7c. Purification of the crude product wasaccomplished using flash chromatography on silica gel eluted withhexane/ethyl acetate (1:2) to give 0.069 g (71%) of the title compoundas a yellow oil. ¹ H NMR (CDCl₃, 300 MHz), δ: 1.55 (3 H), 3.85 (q, 1 H),5.11 (s, 2 H), 5.67 (s, 2 H), 7.27-7.80 (m, 9 H).

EXAMPLE 173-O-Nitroso-hydroxymethylene-(1-(3-benzoyl-α-methylbenzeneacetic acid))benzyl ester

17a. 3-Hydroxymethylene-(1-(3-benzoyl-α-methylbenzeneacetic acid))benzyl ester

Under a nitrogen atmosphere, 1,3-benzenedimethanol (0.500 g, 3.62 mmol)and pyridine (0.193 g, 2.44 mmol) were combined in methylene chloride (7mL). The resulting solution was stirred for 5 minutes and then cooled to0 C. A solution of the the product of Example 16a (0.665 g, 2.44 mmol)in methylene chloride (5 mL) was added dropwise over 15 minutes. Thereaction mixture was stirred 2 h 30 min at 0° C. concentrated in vacuo,diluted with ethyl acetate, washed with 1N hydrochloric acid andsaturated sodium bicarbonate solution. The organic phase was dried overanhydrous sodium sulfate and concentrated in vacuo. The residue waspurified by flash chromatography on silica gel eluting with hexane/ethylacetate (2:1) to give 0.530 g (58%) of the product. ¹ H NMR (CDCl₃) δ:1.55 (δ: 3 H), 3.85 (q, 1 H), 4.64 (s, 2 H), 5.12 (d, 2 H), 7.13-7.18(m, 1 H), 7.22 (s, 1 H), 7.26-7.30 (m, 2 H), 7.40-7.67 (m, 6 H), 773-7.78 (m, 3 H).

17b. 3-O-Nitroso-hydroxymethylene-(1-(3-benzoyl-α-methylbenzeneaceticacid)) benzyl ester

The product of Example 17a (0.74 g, 0.198 mmol) was treated in the samemanner as set forth in Example 7c. Purification of the crude product wasaccomplished using flash chromatography on silica gel eluted withhexane/ethyl acetate (2:1) to give 0.046 g (71%) of the title compound.¹ H NMR (CDCl₃) δ: 1.55 (d, 3 H), 3.85 (q, 1 H), 5.12 (s, 2 H), 5.65 (s,2 H), 7.18-7.31 (m, 4 H), 7.40-7.75 (m, 6 H), 7.76-7.79 (m, 3 H).

EXAMPLE 183-O-Nitroso-hydroxymethylene-1-(1-(3-benzoyl-α-methylbenzeneaceticacid)) -hydroxymethyladamantyl ester

18a. 1,3-Dicarboxymethyl adamantane

1,3-adamantanedicarboxylic acid (1.5 g, 5.95 mmol) was dissolved inmethanol (30 mL) and concentrated sulfuric acid (0.5 mL, 8.90 mmol) wasadded. The reaction mixture was stirred at room temperature for 20hours. After concentration in vacuo, the residue was dissolved inmethylene chloride, washed with water/brine (1:1), and dried overanhydrous sodium sulfate. The solvent was evaporated to give the productas a white solid in a quantitative yield. ¹ H NMR (CDCl₃) δ: 1.65-1.71(m, 2 H), 1.76-1.82 (m, 8 H), 1.98-2.03 (m, 2 H), 2.07-2.18 (m, 2 H),3.66 (s, 6 H).

18b. 1,3-Dihydroxymethyl adamantane

Under a nitrogen atmosphere, the product of Example 18a (1.33 g, 5.95mmol) was dissolved in tetrahydrofuran (20 mL) and lithium aluminumhydride (0.316 g, 8.33 mmol) was added in one portion. The reactionmixture was allowed to reflux for 30 minutes, and was then quenched withwater (0.316 mL, 8.33 mmol), 15% sodium hydroxide solution (0.316 mL),and water (0.95 mL). After 15 hours of stirring at room temperature, thereaction mixture was filtered through PTFE and filtrate was partitionedbetween ethyl acetate and brine. The organic phase was dried overanhydrous sodium sulfate, filtered through PTFE and concentrated invacuo to give the product (0.370 g, 28%) as a white solid. ¹ H NMR(CDCl₃) δ: 1.24-1.29 (m, 2 H), 1.42-1.52 (m, 8 H), 1.61-1.68 (m, 2 H),2.07-2.16 (m, 2 H), 3.25 (s, 4 H).

18c. 3-Hydroxymethylene-1-(1-(3-benzoyl-α-methylbenzeneacetic acid))hydroxymethyladamantyl ester

The product of Example 18b (0.199 g, 0.54 mmol) was dissolved intetrahydrofuran (10 mL) and pyridine (0.047 g, 0.59 mmol) was added Asolution of the product of Example 16a (0.161 g, 0.59 mmol) inchloroform (3 mL) was added dropwise. The reaction mixture was stirredat room temperature for 40 hours. The solvent was evaporated, theresidue was dissolved in methylene chloride, washed with 1N hydrochloricacid, saturated sodium bicarbonate solution and brine, and dried overanhydrous sodium sulfate. The solvent was evaporated and the residue waspurified by flash chromatography on silica gel eluted with hexane/ethylacetate (2:1) to give the product (0.102 g, 28%) as a colorless oil. ¹ HNMR (CDCl₃) δ: 1.13-1.17 (m, 2 H), 1.18-1.55 (m, 10 H), 1.98-2.02 (m, 2H), 3.18 (s, 2 H), 3.66 (d, 1 H), 3.77 (d, 1 H), 3.83 (q, 1 H),7.43-7.68 (m, 6 H), 7.76-7.81 (m, 3 H).

18d. 3-O-Nitroso-hydroxymethylene-1-(1-(3-benzoyl-α-methylbenzeneaceticacid))-hydroxymethyladamantyl ester

The product of Example 18c (0.056 g, 0.083 mmol) was dissolved inanhydrous methylene chloride (2 mL) and pyridine (2 drops) was added.The resulting solution was cooled to -78° C. and nitrosoniumtetrafluoroborate was added in one portion. The reaction mixture wasstirred for 3 hours at -78° C., washed with water, brine, dried overanhydrous sodium sulfate and concentrated in vacuo. The residue waspurified by chromatography on silica gel eluted with hexane/ethylacetate (15:1) to give the title compound as a colorless oil. ¹ H NMR(CDCl₃) δ: 1.15-1.19 (m, 2 H), 1.29-1.61 (m, 10 H), 1.98-2.03 (m, 2 H),3.65 (d, 1 H), 3.77 (d, 1 H), 3.82 (q, 1 H), 4.33 (s, 2 H), 7.43-7.68(m, 6 H), 7.76-7.81 (m, 3 H).

EXAMPLE 19 Comparative In Vivo Analgesic, Antiinflammatory and GastricLesion Activities

The phenylbenzoquinone-induced writhing test in mice was used to measureanalgesic activity. The ability of the compounds to inhibitphenylbenzoquinone-induced writhing in mice was measured using themethod of Siegmund et at., Proc. Soc. Exp. Biol. Med. 95: 729-731, 1957.Male CD-1 mice (Charles River Laboratories, Wilmington, Mass.) weighing20-25 g were fasted overnight Vehicle or compounds were administered byoral gavage 1 hour prior to i.p. injection of 2 mg/kg ofphenylbenzoquinone. In the case of a nitric oxide adduct being given incombination with a NSAID, the nitric oxide adduct was administeredimmediately before the NSAID. Five minutes after the i.p. injection ofphenylbenzoquinone, the number of writhes in a 5 minute period wascounted.

The rat paw edema test was used to measure antiinflammatory activity.The rat paw edema test was performed according to the method of Winteret al., Proc. Soc. Ep. Biol. Med. 111: 544-547, 1962. MaleSprague-Dawley rats (250-275 g) were fasted overnight and dosed by oralgavage with vehicle or suspensions of compound one hour prior to thesubplantar injection of 50 μl of 1% suspension of carrageenin. Threehours later, the paw volume was measured and compared with the initialvolume measured immediately after carrageenin injection.

The rat gastric lesion test (Kitagawa et al., J. Pharmacol. Exp.Ther.,253:1133-1137, 1990; Al-Ghamdi et al., J Int. Med Res., 19: 2242, 1991)was used to evaluate the potential of compounds to produce gastriclesion. Male Sprague Dawley rats (Charles River Laboratories,Wilmington, Mass.) weighing 230-250 g were used for the experiments. Therats were housed with laboratory chow and water ad libitum prior to thestudy. The rats were fasted for 24-30 hours with free access to waterand then dosed by oral gavage with vehicle or with drugs given at avolume of 0.5 mL/100 g. For the unmodified NSAIDs being given incombination with a nitric oxide adduct (NO-adduct), the NO-adduct wasadministered by oral gavage immediately prior to the administration ofNSAID by oral gavage. Food was withheld for 18 hours after the initaldosing. For acute studies, rats were euthanized by CO₂ eighteen hoursafter dosing and the stomachs were dissected. For the multiple dosingstudies, the results of which are in Table 3, food was given eighteenhours after the first dose and the rats were maintained on food andwater ad libitum while receiving a single daily dose for the remainderof the experiment. For the multiple dosing studies, the results of whichare in Table 4, the rats were either fasted 24-30 hours before the firstdosing and for 4 hours after the first dosing, (4 day study withketoprofen, Example 4, and Example 6); allowed access to food and waterad libitum before as well as during the experiment, (7 day study withketoprofen and Example 4); or fasted 24-30 hours prior to the firstdosing and for 18 hours after the first dosing, (7 day study withibuprofen, Example 11, and Example 12). The stomachs were dissectedalong the greater curvature, washed with a directed stream of 0.9%saline and pinned open on a sylgard based petridish for examination ofthe hemorrhagic lesion. Gastric lesion score was expressed in mm andcalculated by summing the length of each lesion.

Table 1 shows the relative activities of compounds in the analgesic,antiinflammatory and gastric lesion tests, and are expressed, for eachnovel NSAID compound, as described according to the general formulas(I), (II), (III) and (IV), or NSAID coadministered with an NO-adduct, asthe ratio of activity relative to the parent NSAID.

                  TABLE 1                                                         ______________________________________                                                Relative Activity                                                     Compound  Analgesia Antiinflammation                                                                           Gastric Lesion                               ______________________________________                                        Ketoprofen                                                                              1         1            1                                            Example 4 1.6       0.58         0.03                                         Example 6 1         ND           ND                                           Example 5 1.1       ND           ND                                           Example 16                                                                              1.1       ND           ND                                           Flurbiprofen                                                                            1         1            1                                            Example 13                                                                              0.31      1.83         0.5                                          Indomethacin                                                                            1         1            1                                            Example 8 1         1            0.08                                         Thuprofen ND        1            1                                            Example 12                                                                              ND        1            <0.03                                        Example 11                                                                              ND        1            <0.05                                        Piroxicam 1         ND           1                                            Piroxicam +                                                                             2.3       ND           0.08                                         Example 2                                                                     ______________________________________                                         ND -- not determined                                                     

Table 2 shows the results of single dose treatment studies in whichvarious NO-adducts were administered in combination with various NSAIDs.The combinations are able to protect against the NSAID induced gastrictoxicity.

                  TABLE 2                                                         ______________________________________                                                                   Molar Dose Gastric                                                            Ratio      Lesion                                  NSAID   (mg/kg) NO-Adduct  NSAID:NO-Adduct                                                                          Protection                              ______________________________________                                        Piroxicam                                                                             16      Example 2  1:1        +++                                     Piroxicam                                                                             8       Example 2  1:1        +++                                     Piroxicam                                                                             8       Isoamyl nitrite                                                                          1:3        +++                                     Piroxicam                                                                             8       Isosorbide 1:3        +++                                                     dinitrate                                                     Piroxicam                                                                             8       Example 1  1:2        +                                       Flurbiprofen                                                                          16      Example 2  1:1        +                                       Tenidap 16      Example 2  1:1        +                                       ______________________________________                                         70-100% Protection =+++; 40-69% Protection = ++; 20-39% Protection =     

Table 3 shows the results of multiple dose treatment studies in whichvarious NO-adducts were administered in combination with various NSAIDs.The combinations are able to protect against the NSAID induced gastrictoxicity.

                  TABLE 3                                                         ______________________________________                                        Treat-                       Molar Dose Gastric                               ment           (mg/          Ratio      Lesion                                (Days)                                                                              NSAID    kg)    NO-Donor                                                                             NSAID:NO-Adduct                                                                          Protection                            ______________________________________                                        3     Piroxicam                                                                              16     Example 2                                                                            1:1        +++                                   14    Piroxicam                                                                              16     Example 2                                                                            1:1        ++                                    7     Thuprofen                                                                              40     Example 2                                                                            1:1        +                                     14    Ibuprofen                                                                              30     Example 2                                                                            1:1        ++                                    ______________________________________                                         70-100% Protection = +++; 40-69% Protection = ++; 20-39% Protection =    

Table 4 shows the results of multiple dose treatment studies in whichvarious novel NSAID compounds directly or indirectly linked to variousNO-adducts were administered. The modified NSAIDs containing NO-adductsproduced significantly less gastric toxcity.

                  TABLE 4                                                         ______________________________________                                                             Treatment                                                                              Relative Gastric                                Compound  (mg/kg)    (Days)   Lesion Activity                                 ______________________________________                                        Ketoprofen                                                                              10         4        +++++                                           Example 4 14         4        +                                               Example 6 15         4        ++                                              Ketoprofen                                                                              10         7        +++++                                           Example 4 14         7        +                                               Ibuprofen 30         7        +++++                                           Example 11                                                                              50         7        +                                               Example 12                                                                              45         7        +                                               Vehicle              7        +                                               ______________________________________                                         100% of the gastric toxcity induced by the parent NSAID = ++++                21-40% of the gastric toxcity induced by the parent NSAID = +                 1-20% of the gastric toxcity induced by the parent NSAID =               

What is claimed is:
 1. A compound of formula I or a pharmaceuticallyacceptable salt thereof: ##STR19## wherein R_(a) is a lower alkyl group,a cycloalkyl group, an aryl group or a heteroaryl group;D is(i) acovalent bond; (ii) --C(R_(a))--O--C(O)--Y--(C(R_(b))(R_(c)))_(p) --T--,wherein R_(a) is a lower alkyl group, a cycloalkyl group, an aryl groupor a heteroaryl group; Y is oxygen, sulfur or NR_(i), wherein R_(i) is ahydrogen atom or a lower alkyl group; R_(b) and R_(c) are eachindependently a hydrogen atom, a lower alkyl group, a cycloalkyl group,an aryl group, a heteroaryl group, an arylalkyl group, an alkylaminogroup or a dialkylamino group, or R_(b) and R_(c) taken together are acycloalkyl group or a bridged cycloalkyl group; p is an integer from 1to 6; and T is a covalent bond, oxygen, sulfur or nitrogen; or (iii)--(CO)--T₁ --(C(R_(b))(R_(c)))_(p) --T₂ --, wherein T₁ and T₂ are eachindependently a covalent bond, oxygen, sulfur or nitrogen; R_(b) andR_(c) are each independently a hydrogen atom, a lower alkyl group, acycloalkyl group, an aryl group, a heteroaryl group, an arylalkyl group,an alkylamino group or a dialkylamino group, or R_(b) and R_(c) takentogether are a cycloalkyl group or a bridged cycloalkyl group; p is aninteger from 1 to 6; Z is an aryl group or a heteroaryl group; and A₁,A₂ and A₃ comprise the other subunits of a 5- or 6-membered monocyclicaromatic ring and each of A₁, A₂ and A₃ is independently:(1) C--R₁wherein R₁ at each occurrence is independently a hydrogen atom, a loweralkyl group, a lower haloalkyl group, an alkoxyalkyl group, a halogenatom or a nitro group; (2) N--R_(d), wherein R_(d) at each occurrence isindependently a covalent bond to an adjacent ring atom in order torender the ring aromatic, a hydrogen atom, a lower alkyl group, acycloalkyl group, an arylalkyl group, an aryl group or a heteroarylgroup; (3) a sulfur atom; (4) an oxygen atom; or (5) B_(a) ═B_(b),wherein B_(a) and B_(b) are each independently a nitrogen atom or C--R₁,wherein R₁ at each occurrence is independently a hydrogen atom, a loweralkyl group, a lower haloalkyl group, an alkoxyalkyl group, a halogenatom or a nitro group.
 2. The compound of claim 1, wherein D is acovalent bond.
 3. The compound of claim 1, wherein D is--C(R_(a))--O--C(O)--Y--(C(R_(b))(R_(c)))_(p) --T--, wherein R_(a) is alower alkyl group, a cycloalkyl group, an aryl group or a heteroarylgroup; Y is oxygen, sulfur or NR_(i), wherein R₁ is a hydrogen atom or alower alkyl group; R_(b) and R_(c) are each independently a hydrogenatom, a lower alkyl group, a cycloalkyl group, an aryl group, aheteroaryl group, an arylalkyl group, an alkylamino group or adialkylamino group, or R_(b) and R_(c) taken together are a cycloalkylgroup or a bridged cycloalkyl group; p is an integer from 1 to 6; and Tis a covalent bond, oxygen, sulfur or nitrogen.
 4. The compound of claim1, wherein D is --(CO)--T₁ --(C(R_(b))(R_(c))_(p) --T₂ --, wherein T₁and T₂ are each independently a covalent bond, oxygen, sulfur ornitrogen; R_(b) and R_(c) are each independently a hydrogen atom, alower alkyl group, a cycloalkyl group, an aryl group, a heteroarylgroup, an arylalkyl group, an alkylamino group or a dialkylamino group,or R_(b) and R_(c) taken together are a cycloalkyl group or a bridgedcycloalkyl group; p is an integer from 1 to
 6. 5. A compositioncomprising the compound of claim 1 and a pharmaceuctically acceptablecarrier.
 6. A composition comprising the compound of claim 1 and acompound that donates, transfers or releases nitric oxide, elevatesendogenous synthesis levels of nitric oxide, or is a substrate fornitric oxide synthase.
 7. The composition of claim 6, wherein thecompound that donates, transfers or releases nitric oxide, elevatesendogenous synthesis levels of nitric oxide, or is a substrate fornitric oxide synthase is L-arginine.
 8. The composition of claim 6,wherein the compound that donates, transfers or releases nitric oxide,elevates endogenous synthesis levels of nitric oxide, or is a substratefor nitric oxide synthase is an S-nitrosothiol.
 9. The composition ofclaim 8, wherein the S-nitrosothiol is S-nitroso-N-acetylcysteine,S-nitroso-N-acetylpenicillamine, S-nitroso-homocysteine,S-nitroso-cysteine or S-nitroso-glutathione.
 10. The composition ofclaim 8, wherein the S-nitrosothiol is:(i) CH₃ (C(R_(b))(R_(c)))_(x)SNO; (ii) HS(C(R_(b))(R_(c)))_(x) SNO; or (iii) ONS(C(R_(b))(R_(c)))_(x)Q;wherein x is 2 to 20; R_(b) and R_(c) are each independently ahydrogen atom, a lower alkyl group, a cycloalkyl group, an aryl group, aheteroaryl group, an arylalkyl group, an alkylamino group or adialkylamino group, or R_(b) and R_(c) taken together are a cycloalkylgroup or a bridged cycloalkyl group; and Q is fluoro, alkoxy, cyano,carboxamido, cycloalkyl, arylalkoxy, alkylsulfinyl, arylthio,alkylamino, dialkylamino, hydroxy, carbamoyl, N-alkylcarbamoyl,N,N-dialkylcarbamoyl, amino, carboxyl, hydrogen, nitro or aryl.
 11. Thecomposition of claim 6, wherein the compound that donates, transfers orreleases nitric oxide, elevates endogenous synthesis levels of nitricoxide, or is a substrate for nitric oxide synthase is:(i) a compoundthat comprises at least one ON--O-- group, ON--N-- group or ON--C--group, wherein the compound that comprises at least one ON--O-- group,ON--N- group or ON--C-- group is an ON--O-polypeptide, anON--N-polypeptide, an ON--C-polypeptide, an ON--O-amino acid, anON--N-amino acid, an ON--C-amino acid, an ON--O-sugar, an ON--N-sugar,an ON--C-sugar, an ON--O-oligonucleotide, an ON--N-oligonucleotide, anON--C-oligonucleotide, an ON--O-heterocyclic compound, anON--N-heterocyclic compound, an ON--C-heterocyclic compound, an ON--O--straight or branched, saturated or unsaturated, substituted orunsubstituted aliphatic or aromatic hydrocarbon, an ON--N-- straight orbranched, saturated or unsaturated, substituted or unsubstitutedaliphatic or aromatic hydrocarbon, or an ON--C--straight or branched,saturated or unsaturated, substituted or unsubstituted aliphatic oraromatic hydrocarbon; (ii) an N-oxo-N-nitrosoamine having the formula R₁R₂ --N(O--M⁺)--NO, wherein R₁ and R₂ are each independently apolypeptide, an amino acid, a sugar, an oligonucleotide, a straight orbranched, saturated or unsaturated, aliphatic or aromatic, substitutedor unsubstituted hydrocarbon group, or a heterocyclic group; and M⁺ is ametal cation; or (iii) a thionitrate having the structure R--(S)_(v)--NO, wherein v is an integer of at least 2, and R is a polypeptide, anamino acid, a sugar, an oligonucleotide, or a straight or branched,saturated or unsaturated, aliphatic or aromatic hydrocarbon.
 12. Thecomposition of claim 6, wherein the compound that donates, transfers orreleases nitric oxide, elevates endogenous synthesis levels of nitricoxide, or is a substrate for nitric oxide synthase is a compoundcomprising at least one --SNO group, wherein the compound comprising atleast one --SNO group is an S-nitroso-polypeptide, an S-nitrosylatedamino acid, an S-nitrosated sugar, an S-nitrosated oligonucleotide, aheterocyclic compound having at least one --SNO group, or a straight orbranched, saturated or unsaturated, substituted or unsubstituted,aliphatic or aromatic S-nitroso hydrocarbon.
 13. A method for treatinginflammation, pain, gastrointestinal lesions or fever in an animal inneed thereof comprising administering the composition of claim 5 to theanimal to treat inflammation, pain, gastrointestinal lesions or fever.14. A method for treating inflammation, pain, gastrointestinal lesionsor fever in an animal in need thereof comprising administering thecomposition of claim 6 to the animal to treat inflammation, pain,gastrointestinal lesions or fever.
 15. A method of reducing thegastrointestinal toxicity or renal toxicity of a nonsteroidalantiinflammatory drug administered to an animal comprising administeringthe composition of claim 5 to the animal to reduce the gastrointestinaltoxicity or renal toxicity of the nonsteroidal antiinflammatory drug.16. A method of reducing the gastrointestinal toxicity or renal toxicityof a nonsteroidal antiinflammatory drug administered to an animalcomprising administering the composition of claim 6 to the animal toreduce the gastrointestinal toxicity or renal toxicity of thenonsteroidal antiinflammatory drug.
 17. A composition comprising anonsteroidal antiinflammatory drug, wherein the nonsteroidalantiinflammatory drug is a compound of formula I or a pharmaceuticallyacceptable salt thereof, and a compound that donates, transfers orreleases nitric oxide, elevates endogenous levels of nitric oxide, or isa substrate for nitric oxide synthase,wherein the compound of formula Iis: ##STR20## wherein R_(a) is a lower alkyl group, a cycloalkyl group,an aryl group or a heteroaryl group; Z is an aryl group or a heteroarylgroup; and A₁, A₂ and A₃ comprise the other subunits of a 5- or6-membered monocyclic aromatic ring and each of A₁, A₂ and A₃ isindependently:(i) C--R₁, wherein R₁ at each occurrence is independentlya hydrogen atom, a lower alkyl group, a lower haloalkyl group, analkoxyalkyl group, a halogen atom or a nitro group; (ii) N--R_(d),wherein R_(d) at each occurrence is independently a covalent bond to anadjacent ring atom in order to render the ring aromatic, a hydrogenatom, a lower alkyl group, a cycloalkyl group, an arylalkyl group, anaryl group or a heteroaryl group; (iii) a sulfur atom; (iv) an oxygenatom; or (v) B_(a) ═B_(b), wherein B_(a) and B_(b) are eachindependently a nitrogen atom or C--R₁, wherein R₁ at each occurrence isindependently a hydrogen atom, a lower alkyl group, a lower haloalkylgroup, an alkoxyalkyl group, a halogen atom or a nitro group.
 18. Thecomposition of claim 17, wherein the compound of formula I is piroxicam,isoxicam, amperoxicam or tenoxicam.
 19. The composition of claim 17,wherein the compound that donates, transfers of releases nitric oxide,elevates endogenous synthesis levels of nitric oxide, or is a substratefor nitric oxide synthase is L-arginine.
 20. The composition of claim17, wherein the compound that donates, transfers or releases nitricoxide, elevates endogenous synthesis levels of nitric oxide, or is asubstrate for nitric oxide synthase is an S-nitrosothiol.
 21. Thecomposition of claim 20, wherein the S-nitrosothiol isS-nitroso-N-acetylcysteine, S-nitroso-N-acetylpenicillamine,S-nitroso-homocysteine, S-nitroso-cysteine or S-nitroso-glutathione. 22.The composition of claim 20, wherein the S-nitrosothiol is:(i) CH₃(C(R_(b))(R_(c)))_(x) SNO; (ii) HS(C(R_(b))(R_(c)))_(x) SNO; or (iii)ONS(C(R_(b))(R_(c)))_(x) Q;wherein x is 2 to 20; R_(b) and R_(c) areeach independently a hydrogen atom, a lower alkyl group, a cycloalkylgroup, an aryl group, a heteroaryl group, an arylalkyl group, analkylamino group or a dialkylamino group, or R_(b) and R_(c) takentogether are a cycloalkyl group or a bridged cycloalkyl group; and Q isfluoro, alkoxy, cyano, carboxamido, cycloalkyl, arylalkoxy,alkylsulfinyl, arylthio, alkylamino, dialkylamino, hydroxy, carbamoyl,N-alkylcarbamoyl, N,N-dialkylcarbamoyl, amino, carboxyl, hydrogen, nitroor aryl.
 23. The composition of claim 17, wherein the compound thatdonates, transfers or releases nitric oxide, elevates endogenoussynthesis levels of nitric oxide, or is a substrate for nitric oxidesynthase is:(i) a compound that comprises at least one ON--O-- group,ON--N-- group or ON--C-- group, wherein the compound that comprises atleast one ON--O-- group, ON--N-- group or ON--C-- group is anON--O-polypeptide, an ON--N-polypeptide, an ON--C-polypeptide, anON--O-amino acid, an ON--N-amino acid, an ON--C-amino acid, anON--O-sugar, an ON--N-sugar, an ON--C-sugar, an ON--O-oligonucleotide,an ON--N-oligonucleotide, an ON--C-oligonucleotide, anON--O-heterocyclic compound, an ON--N-heterocyclic compound, anON--C-heterocyclic compound, an ON--O-- straight or branched, saturatedor unsaturated, substituted or unsubstituted aliphatic or aromatichydrocarbon, an ON--N-- straight or branched, saturated or unsaturated,substituted or unsubstituted aliphatic or aromatic hydrocarbon, or anON--C-- straight or branched, saturated or unsaturated, substituted orunsubstituted aliphatic or aromatic hydrocarbon; (ii) anN-oxo-N-nitrosoamine having the formula R₁ R₂ --N(O--M⁺)--NO, wherein R₁and R₂ are each independently a polypeptide, an amino acid, a sugar, anoligonucleotide, a straight or branched, saturated or unsaturated,aliphatic or aromatic, substituted or unsubstituted hydrocarbon group,or a heterocyclic group; and M⁺ is a metal cation; or (iii) athionitrate having the structure R--(S)_(v) --NO, wherein X is aninteger of at least 2 and R is a polypeptide, an amino acid, a sugar, anoligonucleotide, or a straight or branched, saturated or unsatured,aliphatic or aromatic hydrocarbon.
 24. The composition of claim 17,wherein the compound that donates, transfers or releases nitric oxide,elevates endogenous synthesis levels of nitric oxide, or is a substratefor nitric oxide synthase is a compound comprising at least one --SNOgroup, wherein the compound comprising at least one --SNO group is anS-nitroso-polypeptide, an S-nitrosylated amino acid, an S-nitrosatedsugar, an S-nitrosated oligonucleotide, a heterocyclic compound havingat least one --SNO group, or a straight or branched, saturated orunsaturated, substituted or unsubstituted, aliphatic or aromaticS-nitroso hydrocarbon.
 25. A method for treating inflammation, pain,gastrointestinal lesions or fever in an animal in need thereofcomprising administering the composition of claim 17 to the animal totreat the inflammation, pain, gastrointestinal lesion or fever.
 26. Amethod of reducing the gastrointestinal toxicity or renal toxicity of anonsteroidal antiiflammatory drug administered to an animal comprisingadministering the composition of claim 17 to the animal to reduce thegastrointestinal toxicity or renal toxicity of the nonsteroidalantiinflammatory drug.
 27. A method for accelerating gastrointestinaltissue repair in an animal in need thereof comprising administering tothe animal a therapeutically effective amount of the composition ofclaim
 17. 28. A method for treating inflammatory bowel disease in ananimal in need thereof comprising administering to the animal atherapeutically effective amount of the composition of claim
 17. 29. Amethod for treating an inflammatory disease state or disorder in ananimal in need thereof comprising administering to the animal atherapeutically effective amount of the composition of claim
 17. 30. Themethod of claim 29, wherein the inflammatory disease state or disorderis a reperfusion injury to an ischemic organ, a myocardial infarction,inflammatory bowel disease, rheumatoid arthritis, osteoarthritis,hypertension, psoriasis, an organ transplant rejection, organpreservation, impotence, a radiation-induced injury, asthma,atherosclerosis, thrombosis, platelet aggregation, metastasis,influenza, a stroke, a burn, a trauma, acute pancreatitis,pyelonephritis, hepatitis, an autoimmune disease, insulin-dependentdiabetes mellitus, disseminated intravascular coagulation, a fattyembolism, Alzheimer's disease, an adult respiratory disease, aninfantile respiratory disease, carcinogenesis, or a hemorrhage in aneonate.
 31. A method for accelerating gastrointestinal tissue repair inan animal in need thereof comprising administering to the animal atherapeutically effective amount of the composition of claim
 5. 32. Amethod for treating inflammatory bowel disease in an animal in needthereof comprising administering to the animal a therapeuticallyeffective amount of the composition of claim
 5. 33. A method fortreating an inflammatory disease state or disorder in an animal in needthereof comprising administering to the animal a therapeuticallyeffective amount of the composition of claim
 5. 34. The method of claim33, wherein the inflammatory disease state or disorder is a reperfusioninjury to an ischemic organ, a myocardial infarction, inflammatory boweldisease, rheumatoid arthritis, osteoarthritis, hypertension, psoriasis,an organ transplant rejection, organ preservation, impotence, aradiation-induced injury, asthma, atherosclerosis, thrombosis, plateletaggregation, metastasis, influenza, a stroke, a burn, a trauma, acutepancreatitis, pyelonephritis, hepatitis, an autoimmune disease,insulin-dependent diabetes mellitus, disseminated intravascularcoagulation, a fatty embolism, Alzheimer's disease, an adult respiratorydisease, an infantile respiratory disease, carcinogenesis, or ahemorrhage in a neonate.
 35. A method for accelerating gastrointestinaltissue repair in an animal in need thereof comprising administering tothe animal a therapeutically effective amount of the composition ofclaim
 6. 36. A method for treating inflammatory bowel disease in ananimal in need thereof comprising administering to the animal atherapeutically effective amount of the composition of claim
 6. 37. Amethod for treating an inflammatory disease state or disorder in ananimal in need thereof comprising administering to the animal atherapeutically effective amount of the composition of claim
 6. 38. Themethod of claim 37, wherein the inflammatory disease state or disorderis a reperfusion injury to an ischemic organ, a myocardial infarction,inflammatory bowel disease, rheumatoid arthritis, osteoarthritis,hypertension, psoriasis, an organ transplant rejection, organpreservation, impotence, a radiation-induced injury, asthma,atherosclerosis, thrombosis, platelet aggregation, metastasis,influenza, a stroke, a burn, a trauma, acute pancreatitis,pyelonephritis, hepatitis, an autoimmune disease, insulin-dependentdiabetes mellitus, disseminated intravascular coagulation, a fattyembolism, Alzheimer's disease, an adult respiratory disease, aninfantile respiratory disease, carcinogenesis, or a hemorrhage in aneonate.
 39. The compound of claim 1, wherein the compound of formula Iis a nitroso-substituted piroxicam, a nitroso-substituted isoxicam, anitroso-substituted amperoxicam, or a nitroso-substituted tenoxicam. 40.The composition of claim 17, wherein the compound of formula I is anoxicam compound.
 41. The composition of claim 17, further comprising apharmaceutically acceptable carrier.
 42. A kit comprising thecomposition of claim
 5. 43. A kit comprising the composition of claim 6.44. A kit comprising the composition of claim
 17. 45. A kit comprising anonsteroidal antiinflammatory drug, wherein the nonsteroidalantiinflammatory drug is a compound of formula I or a pharmaceuticallyacceptable salt thereof, and a compound that donates, transfers orreleases nitric oxide, elevates endogenous levels of nitric oxide, or isa substrate for nitric oxide synthase, wherein the compound of formula Iis: ##STR21## wherein R_(a) is a lower alkyl group, a cycloalkyl group,an aryl group or a heteroaryl group;Z is an aryl group or a heteroarylgroup; and A₁, A₂ and A₃ comprise the other subunits of a 5- or6-membered monocyclic aromatic ring and each of A₁, A₂ and A₃ isindependently:(i) C--R₁, wherein R₁ at each occurrence is independentlya hydrogen atom, a lower alkyl group, a lower haloalkyl group, analkoxyalkyl group, a halogen atom or a nitro group; (ii) N--R_(d),wherein R_(d) at each occurrence is independently a covalent bond to anadjacent ring atom in order to render the ring aromatic, a hydrogenatom, a lower alkyl group, a cycloalkyl group, an arylalkyl group, anaryl group or a heteroaryl group; (iii) a sulfur atom; (iv) an oxygenatom; or (v) B_(a) ═B_(b), wherein B_(a) and B_(b) are eachindependently a nitrogen atom or C--R₁, wherein R₁ at each occurrence isindependently a hydrogen atom, a lower alkyl group, a lower haloalkylgroup, an alkoxyalkyl group, a halogen atom or a nitro group.
 46. Thekit of claim 45, wherein the nonsteroidal antiinflammatory drug that isa compound of formula I or the pharmaceutically acceptable salt thereofand the compound that donates, transfers or releases nitric oxide,elevates endogenous levels of nitric oxide, or is a substrate for nitricoxide synthase are separate components in the kit or are in the form ofa composition in the kit.